Formulations of rifaximin and uses thereof

ABSTRACT

The present invention relates to new rifaximin forms comprising solid dispersions of rifaximin, methods of making same and to their use in medicinal preparations and therapeutic methods.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/615,121, filed Jun. 6, 2017 which is a continuation of U.S. patentapplication Ser. No. 14/250,293, filed Apr. 10, 2014 which is acontinuation of U.S. patent application Ser. No. 13/181,481 filed 12Jul. 2011 which claims the benefit of U.S. Provisional Application No.61/363,609 filed 12 Jul. 2010, and U.S. Provisional Application No.61/419,056, filed 2 Dec. 2010, the entire contents of each of which arehereby incorporated herein by reference.

BACKGROUND

Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibioticbelonging to the rifamycin class of antibiotics, e.g., a pyrido-imidazorifamycin. Rifaximin exerts its broad antibacterial activity, forexample, in the gastrointestinal tract against localizedgastrointestinal bacteria that cause infectious diarrhea, irritablebowel syndrome, small intestinal bacterial overgrowth, Crohn's disease,and pancreatic insufficiency among other diseases. It has been reportedthat rifaximin is characterized by a negligible systemic absorption, dueto its chemical and physical characteristics (Descombe J. J. et al.Pharmacokinetic study of rifaximin after oral administration in healthyvolunteers. Int J Clin Pharmacol Res, 14 (2), 51-56, (1994)).

Rifaximin is described in Italian Patent IT 1154655 and EP 0161534, bothof which are incorporated herein by reference in their entirety for allpurposes. EP 0161534 discloses a process for rifaximin production usingrifamycin O as the starting material (The Merck Index, XIII Ed., 8301).U.S. Pat. No. 7,045,620 B1 and PCT Publication WO 2006/094662 A1disclose polymorphic forms of rifaximin. There is a need in the art forformulations of rifaximin to better treat gastrointestinal and otherdiseases.

SUMMARY

Provided herein are solid dispersion forms of rifaximin with a varietyof polymers and polymer concentrations.

In one aspect, provided herein are forms solid dispersion of rifaximin.

In one embodiment, the form solid dispersion of rifaximin ischaracterized by an XRPD substantially similar to one or more of theXRPDs of FIGS. 2, 7, 12, 17, 22, 31, and 36.

In one embodiment, the form solid dispersion of rifaximin ischaracterized by a Thermogram substantially similar to FIGS. 3-6, 8-11,13-16, 18-21, 23-26, 27-30, and 32.

In one embodiment, the form has the appearance of a single glasstransition temperature (Tg).

In one embodiment, a Tg of a form increases with an increased rifaximinconcentration. In one embodiment, a form stressed at 70° C./75% RH for 1week, solids are still x-ray amorphous according to XRPD.

In one embodiment, a form stressed at 70° C./75% RH for 3 weeks, solidsare still x-ray amorphous according to XRPD.

In one embodiment, a form stressed at 70° C./75% RH for 6 weeks, solidsare still x-ray amorphous according to XRPD.

In one embodiment, a form stressed at 70° C./75% RH for 12 weeks, solidsare still x-ray amorphous according to XRPD.

In one aspect, provided herein are microgranules comprising one or moreof the solid dispersion forms of rifaximin described herein.

In one embodiment, the microgranules further comprise a polymer.

In one embodiment, the polymer comprises one or more ofpolyvinylpyrrolidone (PVP) grade K-90, hydroxypropyl methylcellulosephthalate (HPMC-P) grade 55, hydroxypropyl methylcellulose acetatesuccinate (HPMC-AS) grades HG and MG, or a polymethacrylate (Eudragit®L100-55).

In specific embodiments, the microgranules comprises 25-75% polymer,40-60% polymer, or 40-50% polymer. In an exemplary embodiment, themicrogranules comprises 42-44% polymer.

In one embodiment, the microgranules comprise equal amounts of rifaximinand polymer.

In another embodiment, the microgranules further comprising anintragranular release controlling agent. In exemplary embodiments, theintragranular release controlling agent comprises a pharmaceuticallyacceptable excepient, disintegrant, crosprovidone, sodium starchglycolate, corn starch, microcrystalline cellulose, cellulosicderivatives, sodium bicarbonate, and sodium alginate.

In one embodiment, the intragranular release controlling agent comprisesbetween about 2 wt % to about 40 wt % of the microgranule, about 5 wt %to about 20 wt % of the microgranule, or about 10 wt % of themicrogranule.

In another embodiment, the intragranular release controlling agentcomprises a pharmaceutically acceptable disintegrant, e.g., one selectedfrom the group consisting of crosprovidone, sodium starch glycolate,corn starch, microcrystalline cellulose, cellulosic derivatives, sodiumbicarbonate, and sodium alginate.

In another embodiment, the microgranules further comprise a wettingagent or surfactant, e.g., a non-ionic surfactant.

In one embodiment, the non-ionic surfactant comprises between about 2 wt% to about 10 wt % of the microgranule, between about 4 wt % to about 8wt % of the microgranule, or about 5.0 wt % of the microgranule.

In one embodiment, the non-ionic surfactant comprises a poloxamer, e.g.,poloxamer 407 also known as Pluronic F-127.

In another embodiment, the microgranules further comprise anantioxidant.

In exemplary embodiments, the antioxidant is butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT) or propyl gallate (PG).

In another embodiment, the antioxidant comprises between about 0.1 wt %to about 3 wt % of the microgranule or between about 0.5 wt % to about 1wt % of the microgranule.

In another aspect, provided herein are pharmaceutical compositionscomprising the microgranules described herein.

In one embodiment, the pharmaceutical compositions further comprise oneor more pharmaceutically acceptable excepients.

In one embodiment, the pharmaceutical compositions are tablets orcapsules.

In one embodiment, the pharmaceutical compositions comprises adisintegrant.

In one embodiment, the polymer comprises one or more ofpolyvinylpyrrolidone (PVP) grade K-90, hydroxypropyl methylcellulosephthalate (HPMC-P) grade 55, hydroxypropyl methylcellulose acetatesuccinate (HPMC-AS) grades HG and MG, or a polymethacrylate (Eudragit®L100-55).

In one aspect, provided herein are pharmaceutical solid dispersionformulations comprising: rifaximin, HPMC-AS, at a rifaximin to polymerratio of 50:50, a non-ionic, surfactant polyol and a intragranularrelease controlling agent.

In one embodiment, the intragranular release controlling agent comprisesabout 10 wt % of the formulation.

In one aspect, provided herein are processes for producing a soliddispersion of rifaximin comprising: making a slurry of methanol,rifaximin, a polymer and a surfactant; spray drying the slurry; andblending the spray dried slurry with a intragranular release controllingagent.

In one aspect, provided herein are processes for producing a soliddispersion of rifaximin comprising: making a slurry of methanol,rifaximin, HPMC-AS MG and Pluronic F-127; spray drying the slurry; andblending the spray dried slurry with a intragranular release controllingagent.

In one embodiment, the intragranular release controlling agent comprisescroscarmellose sodium.

A process for producing form solid dispersion of rifaximin comprisingone or more of the methods listed in Tables 1-5.

In one embodiment, pharmaceutical compositions comprising SD rifaximin,a polymer, a surfactant, and a release controlling agent are provided.In one embodiment, provided are pharmaceutical compositions comprisingSD rifaximin, HPMC-AS, pluronic F127, and croscarmellose Na (CS). In oneembodiment, the pharmaceutical compositions are tablets or pills.

In additional embodiments, the pharmaceutical compositions furthercomprise fillers, glidants or lubricants.

In specific embodiments, the pharmaceutical compositions comprise theratios of components set forth in Table 37.

Other embodiment and aspects are disclosed infra.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Chemical structure of Rifaximin.

FIG. 2. Overlay of XRPD patterns for Rifaximin/PVP K-90 dispersionsobtained from methanol by spray drying.

FIG. 3. mDSC thermogram for 25:75 (w/w) Rifaximin/PVP K-90 dispersionobtained from methanol by spray drying.

FIG. 4. mDSC thermogram for 50:50 (w/w) Rifaximin/PVP K-90 dispersionobtained from methanol by spray drying.

FIG. 5. mDSC thermogram for 75:25 (w/w) Rifaximin/PVP K-90 dispersionobtained from methanol by spray drying.

FIG. 6. Overlay of mDSC thermogram for Rifaximin/PVP K-90 dispersionsobtained from methanol by spray drying.

FIG. 7. Overlay of XRPD patterns for Rifaximin/HPMC-P dispersionsobtained from methanol by spray drying.

FIG. 8. mDSC thermogram for 25:75 (w/w) Rifaximin/HPMC-P dispersionobtained from methanol by spray drying.

FIG. 9. mDSC thermogram for 50:50 (w/w) Rifaximin/HPMC-P dispersionobtained from methanol by spray drying.

FIG. 10. mDSC thermogram for 75:25 (w/w) Rifaximin/HPMC-P dispersionobtained from methanol by spray drying.

FIG. 11. Overlay of mDSC thermogram for Rifaximin/HPMC-P dispersionsobtained from methanol by spray drying.

FIG. 12. Overlay of XRPD patterns for Rifaximin/HPMC-AS HG dispersionsobtained from methanol by spray drying.

FIG. 13. mDSC thermogram for 25:75 (w/w) Rifaximin/HPMC-AS HG dispersionobtained from methanol by spray drying.

FIG. 14. mDSC thermogram for 50:50 (w/w) Rifaximin/HPMC-AS HG dispersionobtained from methanol by spray drying.

FIG. 15. mDSC thermogram for 75:25 (w/w) Rifaximin/HPMC-AS HG dispersionobtained from methanol by spray drying.

FIG. 16. Overlay of mDSC thermogram for Rifaximin/HPMC-AS HG dispersionsobtained from methanol by spray drying.

FIG. 17. Overlay of XRPD patterns for Rifaximin/HPMC-AS MG dispersionsobtained from methanol by spray drying.

FIG. 18. mDSC thermogram for 25:75 (w/w) Rifaximin/HPMC-AS MG dispersionobtained from methanol by spray drying.

FIG. 19. mDSC thermogram for 50:50 (w/w) Rifaximin/HPMC-AS MG dispersionobtained from methanol by spray drying.

FIG. 20. mDSC thermogram for 75:25 (w/w) Rifaximin/HPMC-AS MG dispersionobtained from methanol by spray drying.

FIG. 21. Overlay of mDSC thermogram for Rifaximin/HPMC-AS MG dispersionsobtained from methanol by spray drying.

FIG. 22. Overlay of XRPD patterns for Rifaximin/Eudragit L100-55dispersions obtained from methanol by spray drying.

FIG. 23. mDSC thermogram for 25:75 (w/w) Rifaximin/Eudragit L100-55dispersion obtained from methanol by spray drying.

FIG. 24. mDSC thermogram for 50:50 (w/w) Rifaximin/Eudragit L100-55dispersion obtained from methanol by spray drying.

FIG. 25. mDSC thermogram for 75:25 (w/w) Rifaximin/Eudragit L100-55dispersion obtained from methanol by spray drying.

FIG. 26. Overlay of mDSC thermogram for Rifaximin/Eudragit L100-55dispersions obtained from methanol by spray drying.

FIG. 27. mDSC thergram for 25:75 (w/w) Rifaximin/HPMC-P dispersionstressed at 40° C./75% RH for 7 d.

FIG. 28. mDSC thergram for 75:25 (w/w) Rifaximin/HPMC-AS HG dispersionstressed at 40° C./75% RH for 7 d.

FIG. 29. mDSC thergram for 75:25 (w/w) Rifaximin/HPMC-AS MG dispersionstressed at 40° C./75% RH for 7 d.

FIG. 30. mDSC thergram for 25:75 (w/w) Rifaximin/Eudragit L100-55dispersion stressed at 40° C./75% RH for 7 d.

FIG. 31. XRPD pattern for 50:50 (w/w) Rifaximin/HPMC-AS MG dispersion.

FIG. 32. Modulate DSC thermograms for 50:50 (w/w) Rifaximin/HPMC-AS MGdispersion.

FIG. 33. TG-IR analysis for 50:50 (w/w) Rifaximin/HPMC-AS MG dispersionTGA data.

FIG. 34. TG-IR analysis for 50:50 (w/w) Rifaximin/HPMC-AS MG dispersionGram-Schmidt plot and waterfall plot.

FIG. 35. TG-IR analysis for 50:50 (w/w) Rifaximin/HPMC-AS MG dispersion.

FIG. 36. XRPD pattern for 25:75 (w/w) Rifaximin/HPMC-P dispersion.

FIG. 37. Modulate DSC thermograms for 25:75 (w/w) Rifaximin/HPMC-Pdispersion.

FIG. 38. TG-IR analysis for 25:75 (w/w) Rifaximin/HPMC-P dispersion—TGAdata.

FIG. 39. TG-IR analysis for 25:75 (w/w) Rifaximin/HPMC-Pdispersion—Gram-Schmidt plot and waterfall plot.

FIG. 40. TG-IR analysis for 25:75 (w/w) Rifaximin/HPMC-P dispersion.

FIG. 41. Overlay of pre-processed XRPD patterns in multivariate mixtureanalysis.

FIG. 42. Estimated Concentrations of Rifaximin (blue) and HPMC-AS MG(red) using Unscrambler MCR analysis.

FIG. 43. Estimated XRPD patterns of Rifaximin (blue) and HPMC-AS MG(red) using Unscrambler MCR analysis.

FIG. 44. Overlay of estimated XRPD pattern of pure rifaximin using MCRand measured XRPD pattern of 100% rifaximin.

FIG. 45. Overlay of estimated XRPD pattern of pure HPMC-AS MG using MCRand measured XRPD pattern of 100% HPMC-AS MG.

FIG. 46. An exemplary XRPD pattern for combined solids ofRifaximin/HPMC-AS MG/Pluronic ternary dispersion.

FIG. 47. A modulate DSC thermogram for combined solids ofRifaximin/HPMC-AS MG/Pluronic ternary dispersion.

FIG. 48. A TG-IR analysis for combined solids of Rifaximin/HPMC-ASMG/Pluronic ternary dispersion—TGA thermogram.

FIG. 49. An exemplary TG-IR analysis for combined solids ofRifaximin/HPMC-AS MG/Pluronic ternary dispersion.

FIG. 50. An exemplary overlay of IR spectra for X-ray amorphousRifaximin and combined solids of Rifaximin/HPMC-AS MG/Pluronic ternarydispersion.

FIG. 51. An exemplary overlay of Ramam spectra for X-ray amorphousRifaximin and combined solids of Rifaximin/HPMC-AS MG/Pluronic ternarydispersion.

FIG. 52. A particle size analysis report for combined solids ofRifaximin/HPMC-AS MG/Pluronic ternary dispersion.

FIG. 53. An exemplary dynamic vapor sorption (DVS) analysis for combinedsolids of Rifaximin/HPMC-AS MG/Pluronic ternary dispersion.

FIG. 54. An exemplary overlay of XRPD patterns for Rifaximin/HPMC-ASMG/Pluronic ternary dispersion post-DVS solids and solids as-prepared.

FIG. 55. An exemplary overlay of XRPD patterns for Rifaximin ternarydispersion post-stressed samples and as-prepared sample.

FIG. 56. An exemplary mDSC thermgram for Rifaximin ternary dispersionafter 70° C./75% RH 1 week.

FIG. 57. An exemplary mDSC thermgram for Rifaximin ternary dispersionafter 70° C./75% RH 3 weeks.

FIG. 58. An exemplary mDSC thermgram for Rifaximin ternary dispersionafter 40° C./75% RH 6 weeks.

FIG. 59. An exemplary mDSC thermgram for Rifaximin ternary dispersionafter 40° C./75% RH 12 weeks.

FIG. 60. Pharmacokinetic data of solid dispersion in dogs.

FIG. 61. Rifaximin SD capsules dissolution; acid phase: 0.1 N HCl withvariable exposure time. Buffer phase: pH 6.8 with 0.45% SDS.

FIG. 62. Rifaximin SD capsules dissolution; acid phase: 2 hours; bufferphase: pH 6.8.

FIG. 63. Rifaximin capsule dissolution; phosphate buffer pH 6.8 with0.45% SDS.

FIG. 64A-D. Rifaximin spray dried dispersion (SDD) capsule dissolution.FIG. 64A acid phase 2 hours, buffer phase: P. Buffer, pH. 7.4. FIG. 64Bacid phase: 0.1N HCl with various exposure times, buffer phase: P.buffer, pH 7.4 with 0.45% SDS. FIG. 64C shows the general structure ofhydroxypropyl methylcellulose (HMPC). FIG. 64D represents the percentreleased at 30 min as a function of pH.

FIG. 65A-B. Rifamixin SDD with 10% CS formulation. FIG. 65A kineticsolubility Rifamixin SD granules. 10% wt % CS sodium FaSSIF, 10% wt % CSsodium FeSSIF. FIG. 65B dissolution profiles SDD tablet 10% CS. 0.2%SLS, pH4.5; 0.2% SLS, pH5.5; 0.2% SLS, pH 7.4; FaSSIF.

FIG. 66A-B. Rifaximin SDD with 10% CS formulation. Rifaxamin SDDcapsules dissolution: FIG. 66A acid phase 2 hours, buffer phase: P.Buffer, pH. 7.4. With 0.45% SDS; without SDS. FIG. 66B acid phase: 0.1NHCl with variable exposure times, buffer phase: P. buffer, pH 7.4 with0.45% SDS.

FIG. 67A-B. Effects of media pH on dissolution. FIG. 67A Rifaxamin SDDtablet dissolution. Acid phase: 2 hours, pH 2.0, FIG. 67B Dissolutionprofiles 0.2% SDS at pH 4.5, SDD tablet dissolution at various levels ofCS: 0%, 2.5%, 5%, and 10% CS.

FIG. 68A-B. Effects of media pH on dissolution. FIG. 68A Rifaxamin SDDtablet dissolution at various levels of CS: 0%, 2.5%, 5%, and 10% CS,0.2% SDS at pH 5.5. FIG. 68B Dissolution profiles SDD tablet dissolutionat various levels of CS: 0%, 2.5%, 5%, and 10% CS, 0.2% SDS at pH 7.4.

FIG. 69A-B. Effects of media pH on dissolution. FIG. 69A Rifaxamin SDDtablet dissolution 2.5% CS, 0.2% SLS, pH4.5, 0.2% SLS, pH 5.5, 0.2% SLS,pH 7.4. FIG. 69B Rifaxamin SDD tablet dissolution 0% CS, 0.2% SLS,pH4.5, 0.2% SLS, pH 5.5, 0.2% SLS, pH 7.4.

FIG. 70A-B. Effects of media pH on dissolution. FIG. 70A Rifaxamin SDDtablet dissolution 10% CS, 0.2% SLS, pH4.5, 0.2% SLS, pH 5.5, 0.2% SLS,pH 7.4. FIG. 70B Rifaxamin SDD tablet dissolution 5% CS, 0.2% SLS,pH4.5, 0.2% SLS, pH 5.5, 0.2% SLS, pH 7.4.

FIG. 71A-B. CS release mechanism. FIG. 71A Kinetic solubility in FaSSIFmedia, pH 6.5, FIG. 71B slope vs. time point.

FIG. 72 depicts an overlay of XRPD patterns of rifaximin quaternarysamples spray dried from methanol. The top is a rifaximin quaternarysample containing 0.063 wt % BHA. The second is rifaximin quaternarysample containing 0.063 wt % BHT. The third: is rifaximin quaternarysample containing 0.094 wt % PG, and the bottom is a spray driedrifaximin ternary dispersion.

FIG. 73 depicts an mDSC thermogram of rifaximin quaternary samplecontaining 0.063 wt % BHA.

FIG. 74 depicts an mDSC thermogram of rifaximin quaternary samplecontaining 0.063 wt % BHT.

FIG. 75 depicts a mDSC thermogram of rifaximin quaternary samplecontaining 0.094 wt % PG.

FIG. 76 depicts an XRPD pattern comparison of rifaximin solid dispersionpowder 42.48% w/w with roller compacted material of rifaximin blend.Top: Rifaximin Solid Dispersion Powder 42.48% w/w; Bottom: rollercompacted rifaximin blend.

FIG. 77 depicts the pharmacokinetics of rifaximin followingadministration of varying forms and formulations following a single oraldose of 2200 mg in dogs.

FIG. 78 depicts Rifaximin SDD in dogs.

FIG. 79 depicts the quotient study design.

FIG. 80 summarizes the dose escalation/regional absorption study, part Adose escalation/dose selection.

FIG. 81 depicts representative subject data from a dose escalationstudy.

FIG. 82 depicts representative subject data from a dose escalationstudy.

FIG. 83 depicts mean dose escalation data, on a linear scale.

FIG. 84 depicts mean dose escalation data, on a log scale.

FIG. 85 depicts a summary of Rifaximin SDD dose escalation studies.

FIG. 86 is a Table of dose/dosage form comparison.

FIG. 87 is a Table of dose/dosage form comparison. This table comparesSDD at increasing doses to the current crystalline formulation in termsof systemic PK.

DETAILED DESCRIPTION

Embodiments described herein relate to the discovery of new soliddispersion forms of rifaximin with a variety of polymers and polymerconcentrations. In one embodiment the use of one or more of new soliddispersion forms of the antibiotic known as Rifaximin (INN), in themanufacture of medicinal preparations for the oral or topical route iscontemplated. For example, the solid dispersion forms of rifaximin areused to create pharmaceutical compositions, e.g., tablets or capsules,or microgranules comprising solid dispersion forms of rifaximin.Exemplary methods for producing rifaximin microgranules are set forth inthe examples. Rifaximin microgranules can be formulated intopharmaceutical compositions as described herein.

Embodiments described herein also relate to administration of suchmedicinal preparations to a subject in need of treatment withantibiotics. Provided herein are solid dispersion forms of rifaximinwith a variety of polymers and polymer concentrations.

As used herein, the term “intragranular release controlling agent”include agents that cause a pharmaceutical composition, e.g., amicrogranule, to breakdown thereby releasing the active ingredient,e.g., rifaximin. Exemplary intragranular release controlling agent,include disintegrants such as crosprovidone, sodium starch glycolate,corn starch, microcrystalline cellulose, cellulosic derivatives, sodiumbicarbonate, and sodium alginate.

In one embodiment, the intragranular release controlling agent comprisesbetween about 2 wt % to about 40 wt % of the microgranule, about 5 wt %to about 20 wt % of the microgranule, about 8-15 wt % or about 10 wt %of the microgranule.

In another embodiment, the microgranule comprises a surfactant, e.g., anon-ionic surfactant. In one embodiment, the non-ionic surfactantcomprises between about 2 wt % to about 10 wt % of the microgranule,between about 4 wt % to about 8 wt % of the microgranule, about 6 toabout 7 wt % of the microgranule, or about 5.0 wt % of the microgranule.

In another embodiment, the microgranule comprises an antioxidant. In oneembodiment, the antioxidant comprises between about 0.1 wt % to about 3wt % of the microgranule, between 0.3 wt % to about 2 wt % or betweenabout 0.5 wt % to about 1 wt % of the microgranule.

As used herein, the term “intragranular” refers to the components thatreside within the microgranule. As used herein, the term “extragranular”refers to the components of the pharmaceutical composition that are notcontained within the microgranule.

As used herein, the term polymorph is occasionally used as a generalterm in reference to the forms of rifaximin and includes within thecontext, salt, hydrate, polymorph co-crystal and amorphous forms ofrifaximin. This use depends on context and will be clear to one of skillin the art.

As used herein, the term “about” when used in reference to x-ray powderdiffraction pattern peak positions refers to the inherent variability ofthe peaks depending on, for example, the calibration of the equipmentused, the process used to produce the polymorph, the age of thecrystallized material and the like, depending on the instrumentationused. In this case the measure variability of the instrument was about±0.2 degrees 2-θ. A person skilled in the art, having the benefit ofthis disclosure, would understand the use of “about” in this context.The term “about” in reference to other defined parameters, e.g., watercontent, C_(max), t_(max), AUC, intrinsic dissolution rates,temperature, and time, indicates the inherent variability in, forexample, measuring the parameter or achieving the parameter. A personskilled in the art, having the benefit of this disclosure, wouldunderstand the variability of a parameter as connoted by the use of theword about.

As used herein, “similar” in reference to a form exhibitingcharacteristics similar to, for example, an XRPD, an IR, a Ramanspectrum, a DSC, TGA, NMR, SSNMR, etc, indicates that the polymorph orcocrystal is identifiable by that method and could range from similar tosubstantially similar, so long as the material is identified by themethod with variations expected by one of skill in the art according tothe experimental variations, including, for example, instruments used,time of day, humidity, season, pressure, room temperature, etc.

As used herein, “rifaximin solid dispersion,” “rifaximin ternarydispersion,” “solid dispersion of rifaximin,” “solid dispersion”, “soliddispersion forms of rifaximin”, “SD”, “SDD”, and “form solid dispersionof rifaximin” are intended to have equivalent meanings and includerifaximin polymer dispersion composition. These compositions are XRPDamorphous, but distinguishable from XRPD of amorphous rifaximin. Asshown in the Examples and Figures, the rifaximin polymer dispersioncompositions are physically chemically distinguishable from amorphousrifaximin, including different Tg, different XRPD profiles and differentdissolution profiles.

Polymorphism, as used herein, refers to the occurrence of differentcrystalline forms of a single compound in distinct hydrate status, e.g.,a property of some compounds and complexes. Thus, polymorphs aredistinct solids sharing the same molecular formula, yet each polymorphmay have distinct physical properties. Therefore, a single compound maygive rise to a variety of polymorphic forms where each form hasdifferent and distinct physical properties, such as solubility profiles,melting point temperatures, hygroscopicity, particle shape, density,flowability, compactibility and/or x-ray diffraction peaks. Thesolubility of each polymorph may vary, thus, identifying the existenceof pharmaceutical polymorphs is essential for providing pharmaceuticalswith predictable solubility profiles. It is desirable to investigate allsolid state forms of a drug, including all polymorphic forms, and todetermine the stability, dissolution and flow properties of eachpolymorphic form. Polymorphic forms of a compound can be distinguishedin a laboratory by X-ray diffraction spectroscopy and by other methodssuch as, infrared spectrometry. For a general review of polymorphs andthe pharmaceutical applications of polymorphs see G. M. Wall, PharmManuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J Pharm. Sci., 58,911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all ofwhich are incorporated herein by reference.

As used herein, “subject” includes organisms which are capable ofsuffering from a bowel disorder or other disorder treatable by rifaximinor who could otherwise benefit from the administration of rifaximinsolid dispersion compositions as described herein, such as human andnon-human animals. The term “non-human animals” includes allvertebrates, e.g., mammals, e.g., rodents, e.g., mice, and non-mammals,such as non-human primates, e.g., sheep, dog, cow, chickens, amphibians,reptiles, etc. Susceptible to a bowel disorder is meant to includesubjects at risk of developing a bowel disorder infection, e.g.,subjects suffering from one or more of an immune suppression, subjectsthat have been exposed to other subjects with a bacterial infection,physicians, nurses, subjects traveling to remote areas known to harborbacteria that causes travelers' diarrhea, subjects who drink amounts ofalcohol that damage the liver, subjects with a history of hepaticdysfunction, etc.

The language “a prophylactically effective amount” of a compositionrefers to an amount of a rifaximin solid dispersion formulation orotherwise described herein which is effective, upon single or multipledose administration to the subject, in preventing or treating abacterial infection.

The language “therapeutically effective amount” of a composition refersto an amount of a rifaximin solid dispersion effective, upon single ormultiple dose administration to the subject to provide a therapeuticbenefit to the subject. In one embodiment, the therapeutic benefit iswounding or killing a bacterium, or in prolonging the survivability of asubject with such a bowel or skin disorder. In another embodiment, thetherapeutic benefit is inhibiting a bacterial infection or prolongingthe survival of a subject with such a bacterial infection beyond thatexpected in the absence of such treatment.

Rifaximin exerts a broad antibacterial activity in the gastrointestinaltract against localized gastrointestinal bacteria that cause infectiousdiarrhea, including anaerobic strains. It has been reported thatrifaximin is characterized by a negligible systemic absorption, due toits chemical and physical characteristics (Descombe J. J. et al.Pharmacokinetic study of rifaximin after oral administration in healthyvolunteers. Int J Clin Pharmacol Res, 14 (2), 51-56, (1994)).

In respect to possible adverse events coupled to the therapeutic use ofrifaximin, the induction of bacterial resistance to the antibiotics isof particular relevance.

From this point of view, any differences found in the systemicabsorption of the forms of rifaximin disclosed herein may besignificant, because at sub-inhibitory concentration of rifaximin, suchas in the range from 0.1 to 1 μg/ml, selection of resistant mutants hasbeen demonstrated to be possible (Marchese A. et al. In vitro activityof rifaximin, metronidazole and vancomycin against Clostridium difficileand the rate of selection of spontaneously resistant mutants againstrepresentative anaerobic and aerobic bacteria, includingammonia-producing species. Chemotherapy, 46(4), 253-266, (2000)).

Forms, formulations and compositions of rifaximin have been found tohave differing in vivo bioavailability properties. Thus, the polymorphsdisclosed herein would be useful in the preparation of pharmaceuticalswith different characteristics for the treatment of infections. Thiswould allow generation of rifaximin preparations that have significantlydifferent levels of adsorption with C_(max) values from about 0.0 ng/mlto 5.0 μg/ml. This leads to preparation of rifaximin compositions thatare from negligibly to significantly adsorbed by subjects undergoingtreatment. One embodiment described herein is modulating the therapeuticaction of rifaximin by selecting the proper form, formulation and/orcomposition, or mixture thereof, for treatment of a subject. Forexample, in the case of invasive bacteria, the most bioavailable form,formulation and/or composition can be selected from those disclosedherein, whereas in case of non-invasive pathogens less adsorbed forms,formulations and/or compositions of rifaximin can be selected, sincethey may be safer for the subject undergoing treatment. A form,formulation and/or composition of rifaximin may determine solubility,which may also determine bioavailability.

For XRPD analysis, accuracy and precision associated with third partymeasurements on independently prepared samples on different instrumentsmay lead to variability which is greater than ±0.1° 2θ. For d-spacelistings, the wavelength used to calculate d-spacings was 1.541874 Å, aweighted average of the Cu-Kα1 and Cu-Kα2 wavelengths. Variabilityassociated with d-spacing estimates was calculated from the USPrecommendation, at each d-spacing, and provided in the respective datatables and peak lists.

Methods of Treatment

Provided herein are methods of treating, preventing, or alleviatingbowel related disorders comprising administering to a subject in needthereof an effective amount of one or more of the solid dispersioncompositions of rifaximin. Bowel related disorders include one or moreof irritable bowel syndrome, diarrhea, microbe associated diarrhea,Clostridium difficile associated diarrhea, travelers' diarrhea, smallintestinal bacterial overgrowth, Crohn's disease, diverticular disease,chronic pancreatitis, pancreatic insufficiency, enteritis, colitis,hepatic encephalopathy, minimal hepatic encephalopathy or pouchitis.

The length of treatment for a particular bowel disorder will depend inpart on the disorder. For example, travelers' diarrhea may only requiretreatment duration of 12 to about 72 hours, while Crohn's disease mayrequire treatment durations from about 2 days to 3 months. Dosages ofrifaximin will also vary depending on the diseases state. Proper dosageranges are provided herein infra. The polymorphs and cocrystalsdescribed herein may also be used to treat or prevent apathology in asubject suspected of being exposed to a biological warfare agent.

The identification of those subjects who are in need of prophylactictreatment for bowel disorder is well within the ability and knowledge ofone skilled in the art. Certain of the methods for identification ofsubjects which are at risk of developing a bowel disorder which can betreated by the subject method are appreciated in the medical arts, suchas family history, travel history and expected travel plans, thepresence of risk factors associated with the development of that diseasestate in the subject. A clinician skilled in the art can readilyidentify such candidate subjects, by the use of, for example, clinicaltests, physical examination and medical/family/travel history.

Topical skin infections and vaginal infections may also be treated withthe rifaximin compositions described herein. Thus, described herein aremethods of using a solid dispersion composition of rifaximin (SDrifaximin compositions) to treat vaginal infections, ear infections,lung infections, periodontal conditions, rosacea, and other infectionsof the skin and/or other related conditions. Provided herein are vaginalpharmaceutical compositions to treat vaginal infection, particularlybacterial vaginosis, to be administered topically, including vaginalfoams and creams, containing a therapeutically effective amount of SDrifaximin compositions, preferably between about 50 mg and 2500 mg.Pharmaceutical compositions known to those of skill in the art for thetreatment of vaginal pathological conditions by the topical route may beadvantageously used with SD rifaximin compositions. For example, vaginalfoams, ointments, creams, gels, ovules, capsules, tablets andeffervescent tablets may be effectively used as pharmaceuticalcompositions containing SD rifaximin compositions, which may beadministered topically for the treatment of vaginal infections,including bacterial vaginosis. Also provided herein are method of usingSD rifaximin compositions to treat gastric dyspepsia, includinggastritis, gastroduodenitis, antral gastritis, antral erosions, erosiveduodenitis and peptic ulcers. These conditions may be caused by theHelicobacter pylori. Pharmaceutical formulations known by those of skillin the art with the benefit of this disclosure to be used for oraladministration of a drug may be used. Provided herein are methods oftreating ear infections with SD rifaximin compositions. Ear infectionsinclude external ear infection, or a middle and inner ear infection.Also provided herein are methods of using SD rifaximin compositions totreat or prevent aspiration pneumonia and/or sepsis, including theprevention of aspiration pneumonia and/or sepsis in patients undergoingacid suppression or undergoing artificial enteral feedings via aGastrostomy/Jejunostomy or naso/oro gastric tubes; prevention ofaspiration pneumonia in patients with impairment of mental status, forexample, for any reason, for subjects undergoing anesthesia ormechanical ventilation that are at high risk for aspiration pneumonia.Provided herein are methods to treat or to prevent periodontalconditions, including plaque, tooth decay and gingivitis. Providedherein are methods of treating rosacea, which is a chronic skincondition involving inflammation of the cheeks, nose, chin, forehead, oreyelids.

Pharmaceutical Preparations

Embodiments also provide pharmaceutical compositions, comprising aneffective amount of one or more SD rifaximin compositions, ormicrogranules comprising SD forms of rifaximin described herein (e.g.,described herein and a pharmaceutically acceptable carrier). In afurther embodiment, the effective amount is effective to treat abacterial infection, e.g., small intestinal bacterial overgrowth,Crohn's disease, hepatic encephalopathy, antibiotic associated colitis,and/or diverticular disease. Embodiments also provide pharmaceuticalcompositions, comprising an effective amount of rifaximin SDcompositions.

For examples of the use of rifaximin to treat Travelers' diarrhea, seeInfante RM, Ericsson C D, Zhi-Dong J, Ke S, Steffen R, Riopel L, Sack DA, DuPont, HL., Enteroaggregative Escherichia coli Diarrhea inTravelers: Response to Rifaximin Therapy. Clinical Gastroenterology andHepatology. 2004; 2:135-138; and Steffen R, M. D., Sack D A, M.D.,Riopel L, PhD, Zhi-Dong J, Ph.D., Sturchler M, M.D., Ericsson C D, M.D.,Lowe B, M. Phil., Waiyaki P, Ph.D., White M, Ph.D., DuPont H L, M. D.Therapy of Travelers' Diarrhea With Rifaximin on Various Continents. TheAmerican Journal of Gastroenterology. May 2003, Volume 98, Number 5, allof which are incorporated herein by reference in their entirety.Examples of treating hepatic encephalopathy with rifaximin see, forexample, N. Engl J Med. 2010_362_1071-1081.

Embodiments also provide pharmaceutical compositions comprisingrifaximin SD compositions and a pharmaceutically acceptable carrier.Embodiments of the pharmaceutical composition further compriseexcipients, for example, one or more of a diluting agent, binding agent,lubricating agent, intragranular release controlling agent, e.g., adisintegrating agent, coloring agent, flavoring agent or sweeteningagent. One composition may be formulated for selected coated anduncoated tablets, hard and soft gelatin capsules, sugar-coated pills,lozenges, wafer sheets, pellets and powders in sealed packet. Forexample, compositions may be formulated for topical use, for example,ointments, pomades, creams, gels and lotions.

In an embodiment, the rifaximin SD composition is administered to thesubject using a pharmaceutically-acceptable formulation, e.g., apharmaceutically-acceptable formulation that provides sustained ordelayed delivery of the SD rifaximin composition to a subject for atleast 2, 4, 6, 8, 10, 12 hours, 24 hours, 36 hours, 48 hours, one week,two weeks, three weeks, or four weeks after thepharmaceutically-acceptable formulation is administered to the subject.The pharmaceutically-acceptable formulations may contain microgranulescomprising rifaximin as described herein.

In certain embodiments, these pharmaceutical compositions are suitablefor topical or oral administration to a subject. In other embodiments,as described in detail below, the pharmaceutical compositions describedherein may be specially formulated for administration in solid or liquidform, including those adapted for the following: (1) oraladministration, for example, drenches (aqueous or non-aqueous solutionsor suspensions), tablets, boluses, powders, granules, pastes; (2)parenteral administration, for example, by subcutaneous, intramuscularor intravenous injection as, for example, a sterile solution orsuspension; (3) topical application, for example, as a cream, ointmentor spray applied to the skin; (4) intravaginally or intrarectally, forexample, as a pessary, cream or foam; or (5) aerosol, for example, as anaqueous aerosol, liposomal preparation or solid particles containing thecompound.

The phrase “pharmaceutically acceptable” refers to those SD rifaximincompositions and cocrystals presented herein, compositions containingsuch compounds, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically-acceptable carrier” includespharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting the subject chemical fromone organ, or portion of the body, to another organ, or portion of thebody. Each carrier is preferably “acceptable” in the sense of beingcompatible with the other ingredients of the formulation and notinjurious to the subject. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Methods of preparing these compositions include the step of bringinginto association a SD rifaximin composition(s) or microgranulescontaining the SD rifaximin compositions with the carrier and,optionally, one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation a SD rifaximin composition with liquid carriers, or finelydivided solid carriers, or both, and then, if necessary, shaping theproduct.

Compositions suitable for oral administration may be in the form ofcapsules, cachets, pills, tablets, lozenges (using a flavored basis,usually sucrose and acacia or tragacanth), powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia) and/or as mouth washes and the like, each containinga predetermined amount of a SD rifaximin composition(s) as an activeingredient. A compound may also be administered as a bolus, electuary orpaste.

The SD compositions of rifaximin disclosed herein can be advantageouslyused in the production of medicinal preparations having antibioticactivity, containing rifaximin, for both oral and topical use. Themedicinal preparations for oral use will contain an SD composition ofrifaximin together with the usual excipients, for example dilutingagents such as mannitol, lactose and sorbitol; binding agents such asstarches, gelatines, sugars, cellulose derivatives, natural gums andpolyvinylpyrrolidone; lubricating agents such as talc, stearates,hydrogenated vegetable oils, polyethylenglycol and colloidal silicondioxide; disintegrating agents such as starches, celluloses, alginates,gums and reticulated polymers; coloring, flavoring, disintegrants, andsweetening agents.

Embodiments described herein include SD rifaximin compositionadministrable by the oral route, for instance coated and uncoatedtablets, of soft and hard gelatin capsules, sugar-coated pills,lozenges, wafer sheets, pellets and powders in sealed packets or othercontainers.

Pharmaceutical compositions for rectal or vaginal administration may bepresented as a suppository, which may be prepared by mixing one or moreSD rifaximin composition(s) with one or more suitable nonirritatingexcipients or carriers comprising, for example, cocoa butter,polyethylene glycol, a suppository wax or a salicylate, and which issolid at room temperature, but liquid at body temperature and,therefore, will melt in the rectum or vaginal cavity and release theactive agent. Compositions which are suitable for vaginal administrationalso include pessaries, tampons, creams, gels, pastes, foams or sprayformulations containing such carriers as are known in the art to beappropriate.

Dosage forms for the topical or transdermal administration of a SDrifaximin composition(s) include powders, sprays, ointments, pastes,creams, lotions, gels, solutions, patches and inhalants. The active SDrifaximin composition(s) may be mixed under sterile conditions with apharmaceutically-acceptable carrier, and with any preservatives,buffers, or propellants which may be required.

Ointments, pastes, creams and gels may contain, in addition to SDrifaximin composition(s), excipients, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof.

Powders and sprays can contain, in addition to a SD rifaximincomposition(s), excipients such as lactose, talc, silicic acid,aluminium hydroxide, calcium silicates and polyamide powder, or mixturesof these substances. Sprays can additionally contain customarypropellants, such as chlorofluorohydrocarbons and volatile unsubstitutedhydrocarbons, such as butane and propane.

The SD rifaximin composition(s) can be alternatively administered byaerosol. This is accomplished by preparing an aqueous aerosol, liposomalpreparation or solid particles containing the compound. A non-aqueous(e.g., fluorocarbon propellant) suspension could be used. Sonicnebulizers are preferred because they minimize exposing the agent toshear, which can result in degradation of the compound.

An aqueous aerosol is made, for example, by formulating an aqueoussolution or suspension of the agent together with conventionalpharmaceutically-acceptable carriers and stabilizers. The carriers andstabilizers vary with the requirements of the particular compound, buttypically include non-ionic surfactants (Tweens, Pluronics, orpolyethylene glycol), innocuous proteins like serum albumin, sorbitanesters, oleic acid, lecithin, amino acids such as glycine, buffers,salts, sugars or sugar alcohols. Aerosols generally are prepared fromisotonic solutions.

Transdermal patches have the added advantage of providing controlleddelivery of a SD rifaximin composition(s) to the body. Such dosage formscan be made by dissolving or dispersing the agent in the proper medium.Absorption enhancers can also be used to increase the flux of the activeingredient across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activeingredient in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of the invention.

Pharmaceutical compositions suitable for parenteral administration maycomprise one or more SD rifaximin composition(s) in combination with oneor more pharmaceutically-acceptable sterile isotonic aqueous ornonaqueous solutions, dispersions, suspensions or emulsions, or sterilepowders which may be reconstituted into sterile injectable solutions ordispersions just prior to use, which may contain antioxidants, buffers,bacteriostats, solutes which render the formulation isotonic with theblood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers which may beemployed in the pharmaceutical compositions include water, ethanol,polyols (such as glycerol, propylene glycol, polyethylene glycol, andthe like), and suitable mixtures thereof, vegetable oils, such as oliveoil, and injectable organic esters, such as ethyl oleate. Properfluidity can be maintained, for example, by the use of coatingmaterials, such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

When the SD rifaximin composition(s) are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% (morepreferably, 0.5 to 90%) of active ingredient in combination with apharmaceutically-acceptable carrier.

Regardless of the route of administration selected, the SD rifaximincomposition(s) are formulated into pharmaceutically-acceptable dosageforms by methods known to those of skill in the art.

Actual dosage levels and time course of administration of the activeingredients in the pharmaceutical compositions may be varied so as toobtain an amount of the active ingredient which is effective to achievethe desired therapeutic response for a particular subject, composition,and mode of administration, without being toxic to the subject. Anexemplary dose range is from 25 to 3000 mg per day. Other doses include,for example, 600 mg/day, 1100 mg/day and 1650 mg/day. Other exemplarydoses include, for example, 1000 mg/day, 1500 mg/day, from between 500mg to about 1800 mg/day or any value in-between.

A preferred dose of the SD rifaximin composition disclosed herein is themaximum that a subject can tolerate without developing serious sideeffects. Preferably, the SD rifaximin composition is administered at aconcentration of about 1 mg to about 200 mg per kilogram of body weight,about 10 to about 100 mg/kg or about 40 mg to about 80 mg/kg of bodyweight. Ranges intermediate to the above-recited values are alsointended to be part. For example, doses may range from 50 mg to about2000 mg/day.

In combination therapy treatment, the other drug agent(s) areadministered to mammals (e.g., humans, male or female) by conventionalmethods. The agents may be administered in a single dosage form or inseparate dosage forms. Effective amounts of the other therapeutic agentsare well known to those skilled in the art. However, it is well withinthe skilled artisan's purview to determine the other therapeutic agent'soptimal effective-amount range. In one embodiment in which anothertherapeutic agent is administered to an animal, the effective amount ofthe rifaximin SD composition is less than its effective amount in casethe other therapeutic agent is not administered. In another embodiment,the effective amount of the conventional agent is less than itseffective amount in case the rifaximin SD composition is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized. Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those skilled in the art.

In various embodiments, the therapies (e.g., prophylactic or therapeuticagents) are administered less than 5 minutes apart, less than 30 minutesapart, 1 hour apart, at about 1 hour apart, at about 1 to about 2 hoursapart, at about 2 hours to about 3 hours apart, at about 3 hours toabout 4 hours apart, at about 4 hours to about 5 hours apart, at about 5hours to about 6 hours apart, at about 6 hours to about 7 hours apart,at about 7 hours to about 8 hours apart, at about 8 hours to about 9hours apart, at about 9 hours to about 10 hours apart, at about 10 hoursto about 11 hours apart, at about 11 hours to about 12 hours apart, atabout 12 hours to 18 hours apart, 18 hours to 24 hours apart, 24 hoursto 36 hours apart, 36 hours to 48 hours apart, 48 hours to 52 hoursapart, 52 hours to 60 hours apart, 60 hours to 72 hours apart, 72 hoursto 84 hours apart, 84 hours to 96 hours apart, or 96 hours to 120 hourspart. In preferred embodiments, two or more therapies are administeredwithin the same subject's visit.

In certain embodiments, one or more compounds and one or more othertherapies (e.g., prophylactic or therapeutic agents) are cyclicallyadministered. Cycling therapy involves the administration of a firsttherapy (e.g., a first prophylactic or therapeutic agent) for a periodof time, followed by the administration of a second therapy (e.g., asecond prophylactic or therapeutic agent) for a period of time,optionally, followed by the administration of a third therapy (e.g.,prophylactic or therapeutic agent) for a period of time and so forth,and repeating this sequential administration, i.e., the cycle in orderto reduce the development of resistance to one of the therapies, toavoid or reduce the side effects of one of the therapies, and/or toimprove the efficacy of the therapies.

In certain embodiments, the administration of the same compounds may berepeated and the administrations may be separated by at least 1 day, 2days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75days, 3 months, or at least 6 months. In other embodiments, theadministration of the same therapy (e.g., prophylactic or therapeuticagent) other than a SD rifaximin composition may be repeated and theadministration may be separated by at least 1 day, 2 days, 3 days, 5days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months,or at least 6 months.

Certain indications may require longer treatment times. For example,travelers' diarrhea treatment may only last from between about 12 hoursto about 72 hours, while a treatment for Crohn's disease may be frombetween about 1 day to about 3 months. A treatment for hepaticencephalopathy may be, for example, for the remainder of the subject'slife span. A treatment for IBS may be intermittent for weeks or monthsat a time or for the remainder of the subject's life.

Compositions and Formulations

Rifaximin solid dispersions, pharmaceutical compositions comprising SDrifaximin or microgranules comprising rifaxmin solid dispersions, can bemade from, for example, polymers including polyvinylpyrrolidone (PVP)grade K-90, hydroxypropyl methylcellulose phthalate (HPMC-P) grade 55,hydroxypropyl methylcellulose acetate succinate (HPMC-AS) grades HG andMG, and a polymethacrylate (Eudragit® L100-55). Rifaximin soliddispersion compositions are comprised of, for example, 10:90, 15:85,20:80, 25:75, 30:70, 40:60, 50:50 60:40, 70:30, 75:25, 80:20, 85:15, and90:10 (Rifaximin/polymer, by weight). Preferred solid dispersions arecomprised of 25:75, 50:50 and 75:25 (Rifaximin/polymer, by weight). Inaddition to rifaximin and polymer, solid dispersions may also comprisesurfactants, for example, non-ionic, surfactant polyols.

An example of a formulation comprises about 50:50 (w/w)Rifaximin:HPMC-AS MG with from between about 2 wt % to about 10 wt % ofa non-ionic, surfactant polyol, for example, Pluronic F-127.

One example of a formulation comprises 50:50 (w/w) Rifaximin:HPMC-AS MGwith about 5.9 wt %) of a non-ionic, surfactant polyol, for example,Pluronic F-127. Spray dried rifaximin ternary dispersion (50:50 (w/w)rifaximin:HPMC-AS MG with 5.9 wt % Pluronic F-127) was blended with 10wt % croscarmellose sodium and then filled into gelatin capsules. Eachcapsule contains 275 mg of rifaximin and the blend formulation is85:5:10 of 50:50 (w/w) Rifaximin:HPMC-AS MG: Pluronic: croscarmellosesodium (calculated in total solids). Other examples of microgranules andpharmaceutical compositions comprising SD rifaximin are described in theexamples.

To form the rifaximin solid dispersion, the components, e.g., rifaximin,polymer and methanol are mixed and then spray dried. Exemplaryconditions are summarized in Table 9 and the procedure outlined belowand in Examples 3 and 4.

Exemplary Spray Drying Process Parameters, include for example:

-   -   Spray Dryer—e.g., PSD 1;    -   Single or multi-fluid nozzle: e.g., a two Fluid Niro Nozzle;    -   Nozzle orifice—0.1-10 mm;    -   Inlet gas temperature—75-150±5 deg C.;    -   Process gas flow (mmH2O)—20-70, preferred 44;    -   Atomizing gas pressure—0.7-1 bar;    -   Feed rate—2-7 kg/Hr;    -   Outlet temperature—30-70±3 deg C.;    -   Solution temperature—20-50 deg C.; and    -   Post spray drying vacuum dry at 20-60 deg C., for between about        2 and 72 hrs.

Article of Manufacture

Another embodiment includes articles of manufacture that comprise, forexample, a container holding a rifaximin SD pharmaceutical compositionsuitable for oral or topical administration of rifaximin in combinationwith printed labeling instructions providing a discussion of when aparticular dosage form should be administered with food and when itshould be taken on an empty stomach. Exemplary dosage forms andadministration protocols are described infra. The composition will becontained in any suitable container capable of holding and dispensingthe dosage form and which will not significantly interact with thecomposition and will further be in physical relation with theappropriate labeling. The labeling instructions will be consistent withthe methods of treatment as described hereinbefore. The labeling may beassociated with the container by any means that maintain a physicalproximity of the two, by way of non-limiting example, they may both becontained in a packaging material such as a box or plastic shrink wrapor may be associated with the instructions being bonded to the containersuch as with glue that does not obscure the labeling instructions orother bonding or holding means.

Another aspect is an article of manufacture that comprises a containercontaining a pharmaceutical composition comprising SD rifaximincomposition or formulation wherein the container holds preferablyrifaximin composition in unit dosage form and is associated with printedlabeling instructions advising of the differing absorption when thepharmaceutical composition is taken with and without food.

Packaged compositions are also provided, and may comprise atherapeutically effective amount of rifaximin. Rifaximin SD compositionand a pharmaceutically acceptable carrier or diluent, wherein thecomposition is formulated for treating a subject suffering from orsusceptible to a bowel disorder, and packaged with instructions to treata subject suffering from or susceptible to a bowel disorder.

Kits are also provided herein, for example, kits for treating a boweldisorder in a subject. The kits may contain, for example, one or more ofthe solid dispersion forms of rifaximin and instructions for use. Theinstructions for use may contain proscribing information, dosageinformation, storage information, and the like.

Packaged compositions are also provided, and may comprise atherapeutically effective amount of an SD rifaximin composition and apharmaceutically acceptable carrier or diluent, wherein the compositionis formulated for treating a subject suffering from or susceptible to abowel disorder, and packaged with instructions to treat a subjectsuffering from or susceptible to a bowel disorder.

The present invention is further illustrated by the following examples,which should not be construed as further limiting. The contents of allfigures and all references, patents and published patent applicationscited throughout this application, as well as the Figures, are expresslyincorporated herein by reference in their entirety.

EXAMPLES

The chemical structure of Rifaximin is shown below in FIG. 1.

Example 1. Solid Dispersions of Rifaximin

Various polymers were formulated with rifaximin into solids prepared bymethanol and spray drying at small scale (˜1 g). Polymers, includingpolyvinylpyrrolidone (PVP) grade K-90, hydroxypropyl methylcellulosephthalate (HPMC-P) grade 55, hydroxypropyl methylcellulose acetatesuccinate (HPMC-AS) grades HG and MG, and a polymethacrylate (Eudragit®L100-55) were used. Solids have compositions of 25:75, 50:50 and 75:25(Rifaximin/polymer, by weight).

Samples generated were observed under polarized light microscope afterpreparation and were characterized by XRPD. The results are included inTable 1 through Table 5. Birefringence with extinction (B/E) was notobserved for any of the samples, indicating solids without crystallineorder were obtained. No sharp peaks were evident by visual inspection ofXRPD patterns of these samples, consistent with non-crystallinematerials, as shown in FIG. 2 (with PVP K-90), FIG. 7 (with HPMC-P),FIG. 12 (with HMPC-AS HG), FIG. 12 (with HMPC-AS MG), and FIG. 17 (withEudragit L100-55).

Materials were characterized by mDSC where the appearance of a singleglass transition temperature (Tg), provides support for anon-crystalline fully miscible dispersion. All the dispersions preparedwith PVP K-90 display a single apparent Tg at approximately 185° C.(FIG. 3, 25:75 w/w), 193° C. (FIG. 4, 50:50 w/w), and 197° C. (FIG. 5,75:25) respectively. The change in heat capacity (ΔCp) at Tg isapproximately 0.3 J/g·° C. for each dispersion. A non-reversibleendotherm, which is likely due to the residual solvent in the materials,was observed in each of Rifaximin/PVP K-90 dispersions centered atapproximately 78° C., 59° C. and 61° C.

From FIG. 6, Tg of Rifaximin/PVP K-90 dispersions increases with theincreased Rifaximin concentration, which is due to the higher Tg ofRifaximin (199° C.) than PVP K-90 (174° C.). Evidence of a single Tg maysuggest that the components of the dispersion are intimately mixed, ormiscible.

Dispersions prepared with other polymers also display a single apparentTg, as a step change in the reversing heat flow signal by mDSC.Dispersions prepared with HPMC-P exhibit Tg at 153° C. (FIG. 8, 25:75w/w), 161° C. (FIG. 9, 50:50 w/w) and 174° C. (FIG. 10, 75:25 w/w)respectively, with ΔCp at Tg approximately 0.4 J/g·° C.

With HPMC-AS HG, dispersions display Tg at 137° C. (FIG. 13, 25:75 w/w),154° C. (FIG. 14, 50:50 w/w) and 177° C. (FIG. 15, 75:25 w/w)respectively; ΔCp at Tg is approximately 0.4 or 0.3 J/g·° C.

With HPMC-AS MG, dispersions display Tg at 140° C. (FIG. 18, 25:75 w/w),159° C. (FIG. 19, 50:50 w/w) and 177° C. (FIG. 10, 75:25 w/w)respectively; ΔCp at Tg is approximately 0.4 or 0.3 J/g·° C.

Dispersions prepared with Eudragit L100-55 exhibit Tg at 141° C. withΔCp approximately 0.5 J/g·° C. (FIG. 23, 25:75 w/w), 159° C. with ΔCpapproximately 0.3 J/g·° C. (FIG. 24, 50:50 w/w), and 176° C. with ΔCp atTg approximately 0.2 J/g·° C. (FIG. 25, 75:25 w/w) respectively.

Similarly, as shown in FIG. 11 (with HPMC-P), FIG. 16 (with HPMC-AS HG),FIG. 21 (with HPMC-AS MG, and FIG. 26 (with Eudragit L100-55), Tg ofmaterial in each set of Rifaximin/polymer dispersions increases with theincreased Rifaximin concentration due to the higher Tg of Rifaximin.

Physical Stability Assessment

An assessment of physical stability for rifaximin/polymer dispersionswas conducted under stress conditions of aqueous solutions at differentbiologically relevant conditions, including 0.1N HCl solution at 37° C.and pH 6.5 FASSIF buffer at 37° C., elevated temperature/relativehumidity (40° C./75% RH), and elevated temperature/dry (60° C.). Thex-ray amorphous rifaximin—only sample prepared from methanol by spraydrying was also stressed under the same conditions for comparison.

Stress in 0.1N HCl Solution at 37° C.

For the assessment of physical stability for samples in a 0.1N HClsolution maintained at 37° C., observations were made and microscopyimages were acquired using polarized light at different time pointsincluding 0, 6 and 24 hrs, as summarized in Table 6. Based on theabsence of birefringent particles when samples were observed by PLM,dispersions prepared with HPMC-AS HG and HPMC-AS MG display the highestphysical stability under this particular stress condition. The resultsof this study for each of samples are discussed below.

X-ray amorphous Rifaximin stressed in 0.1N HCl solution at 37° C. at 0,6, and 24 hrs showed evidence of birefringence/extinctions was observedat 6 hrs, indicating the occurrence of devitrification of the material.

Samples at compositions of 25:75 and 50:50 (w/w) crystallized at 6 hrs;sample at 75:25 (w/w) composition crystallized within 24 hrs while noevidence of crystallization was observed at 6 hrs or earlier. Thedecreased stability of Rifaximin/PVP K-90 dispersions in 0.1N HClsolution with increased PVP K-90 concentration may due to the highsolubility of PVP K-90 in the solution.

Irregular aggregates without birefringence/extinctions were observed fordispersion prepared with HPMC-P at t=0 hr, the initial time point when0.1N HCl solution was just added into solids. After 24 hrs, samples atcompositions of 25:75 and 50:50 (w/w) remained as non-birefringentaggregates, indicating no occurrence of devitrification under theconditions examined. Evidence of crystallization was observed for sampleof 75:25 (w/w) composition at 6 hrs. No birefringence/extinctions wereobserved for all of dispersions prepared with HPMC-AS HG and HPMC-AS MGafter 24 hrs, suggesting these samples are resistant to devitrificationupon exposure to 0.1N HCl solution for 24 hrs.

For dispersions prepared with Eudragit L100-55, upon exposure to 0.1NHCl solution for 24 hrs, birefringent particles with extinctions wereobserved only in the sample at 50:50 (w/w) composition. Considered thatno evidence of crystallization was observed for dispersions ofcompositions at 25:75 and 75:25 (w/w), it is unknown whether suchbirefringence was caused by some foreign materials or by crystallinesolids indicating the occurrence of devitrification.

Stress in pH 6.5 FASSIF Buffer at 37° C.

An assessment of physical stability of dispersions prepared was alsoperformed in pH 6.5 FASSIF buffer maintained at 37° C. X-ray amorphousRifaximin material was also stressed under same condition forcomparison. PLM observations indicated that dispersions prepared fromHPMC-AS HG and HPMC-AS MG display the highest physical stability underthis stress condition. X-ray amorphous rifaximin-only materialcrystallized within 6 hrs, so did all rifaximin/PVP K-90 dispersions.For dispersions prepared with HPMC-P, birefringent particles withextinctions were observed in samples at 50:50 and 75:25 (w/w)compositions within 6 hrs, indicating the occurrence of devitrificationin materials. No evidence of any birefringence/extinctions was observedin 25:75 (w/w) rifaximin/HPMC-P dispersion material after 24 hrs. Nobirefringence/extinctions were observed for all of dispersions preparedwith HPMC-AS HG and HPMC-AS MG after 24 hrs, suggesting these samplesare resistant to devitrification upon exposure to pH 6.5 FASSIF bufferfor 24 hrs. Rifaximin/Eudragit L100-55 dispersions at 50:50 and 75:25(w/w) compositions crystallized with 6 hrs while no evidence ofcrystallization was observed in the sample at 25:75 (w/w) compositionafter 24 hrs.

Stress at 40° C./75% RH Condition

The samples including all the dispersions and x-ray amorphousrifaximin-only material were assessed for evidence of crystallizationbased on observations by microscopy using polarized light. Each of thesamples remained as irregular aggregates withoutbirefringence/extinctions after stressed at 40° C./75% RH condition for7 days.

Modulated DSC analyses were carried out on selected samples including25:75 (w/w) rifaximin/HPMC-P, 75:25 (w/w) rifaximin/HPMC-AS HG, 75:25(w/w) rifaximin/HPMC-AS MG, and 25:75 (w/w) Rifaximin/Eudragit L100-55to inspect for evidence of phase separation after exposure to 40° C./75%RH for 7 days. All of samples display a single apparent Tg atapproximately 148° C. (FIG. 27, 25:75 (w/w) HPMC-P), 177° C. (FIG. 28,75:25 (w/w) HPMC-AS HG) 152° C. (FIG. 29, 75:25 (w/w) HPMC-AS MG) and140° C. (FIG. 30, 25:75 (w/w) Eudragit L100-55) respectively, indicatingthe components of each dispersion remained intimately miscible afterstress. Although crimped with manual pin-hole DSC pan was used, therelease of moisture from sample upon heating can still be observed fromnon-reversible heat flow signals.

Stress at 60° C./Dry Condition

All the dispersions and x-ray amorphous rifaximin-only material werealso stressed at 60° C./dry condition for 7 days and were assessed forevidence of crystallization based on observations by microscopy usingpolarized light. Each of the samples remained as irregular aggregateswithout birefringence/extinctions after stressed at this condition for 7days.

Rifaximin Solid Dispersions by Spray Drying

Based on the experimental results from screen, HPMC-AS MG and HPMC-Pwere used to prepare additional quantities of solid dispersions atgram-scale by spray drying. The operating parameters used for processingare presented in Table 9. Based on visual inspection, both dispersionswere x-ray amorphous by XRPD (FIG. 31 and FIG. 36).

Characterization of 50:50 (w/w) Rifaximin/HPMC-AS MG Dispersion

Characterization and results for the 50% API loading HPMC-AS MG aresummarized in Table 10. The sample was x-ray amorphous based on highresolution XRPD. A single Tg at approximately 154° C. was observed fromthe apparent step change in the reversing heat flow signal in mDSC withthe change of heat capacity 0.4 J/g ° C. A non-reversible endotherm wasobserved at approximately 39° C. which is likely due to the residualsolvent in the materials (FIG. 32). TG-IR analysis was carried out inorder to determine volatile content on heating. TGA data for thismaterial is shown in FIG. 34. There was a 0.5% weight loss up to ˜100°C. A Gram-Schmidt plot corresponding to the overall IR intensityassociated with volatiles released by solids upon heating at 20° C./minis shown in FIG. 33. There was a dramatic increase of intensity ofreleased volatiles after ˜8 minutes, with a maximum at ˜11.5 minutes.The waterfall plot (FIG. 34) and the linked IR spectrum (FIG. 35) areindicative of the loss of water loss up to −8 minutes then methanol andsome unknown volatiles thereafter. This is consistent with the dramaticchange in the slope in the TGA and may indicate decomposition ofmaterial.

Characterization of 25:75 (w/w) Rifaximin/HPMC-P Dispersion

Characterization and results for the 25% API loading dispersion ofHPMC-P are summarized in Table 11. Solids were x-ray amorphous based onhigh resolution XRPD (FIG. 36). By mDSC, there is a single Tg atapproximately 152° C. from the apparent step change in the reversingheat flow signal. The change of heat capacity is 0.4 J/g ° C. (FIG. 37).A non-reversible endotherm, which is likely due to the residual solventin the materials, was observed at approximately 46° C. Volatilesgenerated on heating were analyzed by TG-IR. The total weight loss ofsample was approximately 1.5 wt % to 100° C. and the dramatic change inthe slope occurs at approximately 178° C. (FIG. 38). The Gram-Schmidtplot (FIG. 39) shows a small increase of intensity upon heating after ˜2minutes, followed by negligible change of intensity until ˜9 minutes.Then dramatic change of intensity can be observed with a maximum at ˜11minutes, followed by a final increase of intensity above ˜12 minutes. Asseen in the waterfall plot (FIG. 39), some volatiles were releasedduring entire heating period (data is shown in FIG. 40 using the linkedIR spectrum at different time points as an example). The sample releasedwater during entire heating period and methanol after ˜9 minutes.

Dispersions Miscibility Study by Multivariate Mixture Analysis

For Rifaximin/HPMC-AS MG dispersions prepared by spray drying, amultivariate mixture analysis was performed using the XRPD data toexamine the physical state of the components and inspect for evidence ofmiscibility. The analysis was done with MATLAB (v7.6.0) and Unscrambler(v 9.8) and it was not performed under cGMP guidelines. XRPD patterns ofall the samples were truncated with their baseline corrected, and unitarea normalized before analysis. The pre-possessed XRPD patterns areshown in FIG. 41.

In the analysis, Rifaximin and HPMC-AS MG were assumed to be separatedphases (no miscibility) and the compositions of Rifaximin and HPMC-AS MGin each sample were estimated based on this assumption. As shown in FIG.42, the estimated ratios of Rifaximin to HPMC-AS MG based on pureseparated phases did not agree with samples actual compositions,especially for the samples with high compositions of HPMC-AS MG (lowRifaximin loading). Also, the calculated XRPD patterns for Rifaximin andHMPC-AS MG based on the assumption of separated phases (FIG. 43)compared to actual experimental XRPD patterns for Rifaximin (FIG. 44)and HPMC-AS MG (FIG. 45) were generated. Although the calculatedRifaximin pattern is similar to its experimental pattern, the calculatedHMPC-AS MG pattern is quite different from its experimental pattern.Both results suggest that Rifaximin and HPMC-AS MG are not separatedphases but miscible in the dispersions. The differences in the estimatedand actual compositions are likely due to the interaction betweenRifaximin and HPMC-AS MG.

TABLE 1 Solid Dispersion Attempts for Rifaximin/PVP K-90 by Spray DryingDescription (a, b) Habit/Description Analysis Result (c) (25:75) solidsorange; XRPD x-ray amorph. PVP K-90 aggregates, irregular, mDSC 185° C.(T_(g), no B/E midpoint); 0.3 J/g · ° C. (ΔC_(p)) (50:50) solids orange;XRPD x-ray amorph. PVP K-90 aggregates, irregular, mDSC 193° C. (T_(g),no B/E midpoint); 0.3 J/g · ° C. (ΔC_(p)) (75:25) solids orange; XRPDx-ray amorph. PVP K-90 aggregates, irregular, mDSC 197° C. (T_(g), noB/E midpoint); 0.3 J/g · ° C. (ΔC_(p)) (a): approximate ratio ofRifaximin to polymer, by weight; (b): samples stored in freezer overdesiccant after prepared.

TABLE 2 Solid Dispersion Attempts for Rifaximin/HPMC-P by Spray DryingDescription (a, b) Habit/Description Analysis Result (c) (25:75) solidslight orange; XRPD x-ray amorph. HPMC-P aggregates, irregular, mDSC 153°C. (T_(g), midpoint); no B/E 0.4 J/g · ° C. (ΔC_(p)) (50:50) solidsorange; XRPD x-ray amorph. HPMC-P aggregates, irregular, mDSC 161° C.(T_(g), midpoint); no B/E 0.4 J/g · ° C. (ΔC_(p)) (75:25) solids orange;XRPD x-ray amorph. HPMC-P aggregates, irregular, mDSC 174° C. (T_(g),midpoint); no B/E 0.4 J/g · ° C. (ΔC_(p)) (a): approximate ratio ofRifaximin to polymer, by weight; (b): samples stored in freezer overdesiccant after prepared.

TABLE 3 Solid Dispersion Attempts for Rifaximin/HPMC-AS HG by SprayDrying Description (a, b) Habit/Description Analysis Result (c) (25:75)solids light orange; XRPD x-ray amorph. HPMC-AS HG aggregates,irregular, mDSC 137° C. (T_(g), no B/E midpoint); 0.4 J/g · ° C.(ΔC_(p)) (50:50) solids orange; XRPD x-ray amorph. HPMC-AS HGaggregates, irregular, mDSC 154° C. (T_(g), no B/E midpoint); 0.4 J/g ·° C. (ΔC_(p)) (75:25) solids orange; XRPD x-ray amorph. HPMC-AS HGaggregates, irregular, mDSC 177° C. (T_(g), no B/E midpoint); 0.3 J/g ·° C. (ΔC_(p)) (a): approximate ratio of Rifaximin to polymer, by weight;(b): samples stored in freezer over desiccant after prepared.

TABLE 4 Solid Dispersion Attempts for Rifaximin/HPMC-AS MG by SprayDrying Description (a, b) Habit/Description Analysis Result (c) (25:75)solids light orange; XRPD x-ray amorph. HPMC-AS MG aggregates, mDSC 140°C. (T_(g), midpoint); irregular, no B/E 0.4 J/g · ° C. (ΔC_(p)) (50:50)solids orange; XRPD x-ray amorph. HPMC-AS MG aggregates, mDSC 159° C.(T_(g), midpoint); irregular, no B/E 0.4 J/g · ° C. (ΔC_(p)) (75:25)solids orange; XRPD x-ray amorph. HPMC-AS MG aggregates, mDSC 177° C.(T_(g), midpoint); irregular, no B/E 0.3 J/g · ° C. (ΔC_(p)) (a):approximate ratio of Rifaximin to polymer, by weight; (b): samplesstored in freezer over desiccant after prepared.

TABLE 5 Solid Dispersion Attempts for Rifaximin/Eudragit L100-55 bySpray Drying Description (a, b) Habit/Description Analysis Result (c)(25:75) solids light orange, XRPD x-ray amorph. Eudragit L100-55aggregates, mDSC 141° C. (T_(g), irregular, no B/E midpoint); 0.5 J/g ·° C. (ΔC_(p)) (50:50) solids orange; XRPD x-ray amorph. Eudragit L100-55aggregates, mDSC 159° C. (T_(g), irregular, no B/E midpoint); 0.3 J/g ·° C. (ΔC_(p)) (75:25) solids orange; XRPD x-ray amorph. Eudragit L100-55aggregates, mDSC 176° C. (T_(g), irregular, no B/E midpoint); 0.2 J/g ·° C. (ΔC_(p)) (a): approximate ratio of Rifaximin to polymer, by weight;(b): samples stored in freezer over desiccant after prepared.

TABLE 6 Physical Stability Assessment in 0.1N HCl at 37° C. forRifaximin and Rifaximin Dispersions Prepared in Methanol by Spray DryingDescription Time (a) (b) Habit/Description Analysis Results (100:0) 0 —PLM agg., irr., no B/E Rifaximin- agg., irr., no B/E only  6 hrs orangesolids, no PLM agg., no B/E + a liquid left few B/E particles clear viewof B/E particles 24 hrs orange solids, PLM agg., no B/E + a solutioncloudy few B/E particles (25:75) 0 — PLM agg., irr., no B/E PVP K-90agg., irr., no B/E  6 hrs orange solids, PLM agg., no B/E + solutionslightly B/E particles yellow clear view of B/E particles 24 hrs orangesolids, PLM agg., no B/E + solution slightly B/E particles yellow(50:50) 0 — PLM agg., irr., no B/E PVP K-90 agg., irr., no B/E  6 hrsorange solids, PLM agg., no B/E + a solution slightly few B/E particlesyellow clear view of B/E particles 24 hrs orange solids, PLM majorityagg., small amount of no B/E + liquid left a few B/E particles clearview of B/E particles (75:25) 0 — PLM agg., irr., no B/E PVP K-90 agg.,irr., no B/E  6 hrs orange solids, PLM agg., no B/E solution slightlyagg., no B/E yellow 24 hrs orange solids, PLM agg., no B/E small amountof a few B/E particles liquid left in view field (25:75) 0 — PLM agg.,irr., no B/E HPMC-P agg., irr., no B/E  6 hrs light orange solids, PLMagg., no B/E liquid turbid agg., no B/E 24 hrs orange solids, PLM agg.,no B/E liquid turbid agg., no B/E (50:50) 0 — PLM agg., irr., no B/EHPMC-P agg., irr., no B/E  6 hrs orange solids, PLM agg., no B/E liquidturbid agg., no B/E 24 hrs orange solids, PLM agg., no B/E solutioncloudy agg., no B/E (75:25) 0 — PLM agg., irr., no B/E HPMC-P agg.,irr., no B/E  6 hrs orange solids, PLM agg., no liquid turbid B/E + someB/E particles clear view of B/E particles 24 hrs orange solids, PLM B/Eparticles small amount of observed liquid left clear view of B/Eparticles (25:75) 0 — PLM agg., irr., no B/E HPMC-AS agg., irr., no B/EHG  6 hrs light orange PLM no B/E observed solids in no B/E observedcloudy liquid 24 hrs orange solids in PLM no B/E observed cloudysolution no B/E observed (50:50) 0 — PLM agg., irr., no B/E HPMC-ASagg., irr., no B/E HG  6 hrs orange solids, PLM no B/E observed liquidcloudy no B/E observed 24 hrs orange solids in PLM no B/E observedcloudy solution (75:25) 0 — PLM agg., irr., no B/E HPMC-AS agg., irr.,no B/E HG  6 hrs orange solids, PLM no B/E observed liquid turbid no B/Eobserved 24 hrs orange solids + PLM agg., no B/E cloudy solution agg.,no B/E (25:75) 0 — PLM agg., irr., no B/E HPMC-AS agg., irr., no B/E MG 6 hrs light orange PLM no B/E observed solids in cloudy liquid 24 hrsorange solids in PLM majority no B/E, a cloudy liquid few B/E particlesB/E particles seems fiber-like, may due to foreign materials (50:50) 0 —PLM agg., irr., no B/E HPMC-AS agg., irr., no B/E MG  6 hrs orangesolids, PLM agg., no B/E + liquid turbid a few B/E particles seems dueto foreign material clear view of B/E particles 24 hrs orange solids inPLM no B/E observed cloudy solution no B/E observed (75:25) 0 — PLMagg., irr., no B/E HPMC-AS agg., irr., no B/E MG  6 hrs orange solids,PLM no B/E observed liquid turbid no B/E observed 24 hrs orange solidsin PLM no B/E observed cloudy liquid agg., no B/E (25:75) 0 — PLM agg.,irr., no B/E Eudragit agg., irr., no B/E L100-55  6 hrs light orange PLMno B/E observed solids in cloudy liquid 24 hrs orange solids in PLM noB/E observed cloudy solution (50:50) 0 — PLM agg., irr., no B/E Eudragitagg., irr., no B/E L100-55  6 hrs orange solids in PLM no B/E observedcloudy liquid except 2 particles 24 hrs orange solids in PLM majority noB/E, a cloudy solurion few B/E particles in center clear view of B/Eparticles (75:25) 0 — PLM agg., irr., no B/E Eudragit agg., irr., no B/EL100-55  6 hrs orange solids, PLM agg., no B/E liquid turbid agg., noB/E 24 hrs orange solids in PLM agg., no B/E cloudy liquid (a):approximate ratio of Rifaximin to polymer, by weight. (b): time iscumulative and approximate; 100 μL of 0.1N HCl solution added intosamples at t = 0. (c): 100 μL of 0.1N HCl solution added into the sampleafter PLM analysis at 6 hrs.

TABLE 7 Physical Stability Assessment at 40° C./75% RH/7 d Condition forRifaximin and Rifaximin Dispersions Prepared in Methanol by Spray DryingDescription (a) Habit/Description Analysis Results (100:0) orangesolids, dry PLM agg., irr., no B/E Rifaximin-only (25:75) dark yellowsolids, PLM agg., irr., no B/E PVP K-90 dry (50:50) orange solids, dryPLM agg., irr., no B/E PVP K-90 (75:25) orange solids, dry PLM agg.,irr., no B/E PVP K-90 (25:75) light orange solids, PLM agg., irr., noB/E HPMC-P dry mDSC 148° C. (T_(g), midpoint); 0.3 J/g · ° C. (ΔC_(p))(50:50) orange solids, dry PLM agg., irr., no B/E HPMC-P (75:25) orangesolids, dry PLM agg., irr., no B/E HPMC-P (25:75) light orange solids,PLM agg., irr., no B/E HPMC-AS HG dry (50:50) orange solids, dry PLMagg., irr., no B/E HPMC-AS HG (75:25) orange solids, dry PLM agg., irr.,no B/E HPMC-AS HG mDSC 177° C. (T_(g), midpoint); 0.5 J/g · ° C.(ΔC_(p)) (25:75) light orange solids, PLM agg., irr., no B/E HPMC-AS MGdry (50:50) orange solids, dry PLM agg., irr., no B/E HPMC-AS MG (75:25)orange solids, dry PLM agg., irr., no B/E HPMC-AS MG mDSC 152° C.(T_(g), midpoint) (25:75) light orange solids, PLM agg., irr., no B/EEudragit dry mDSC 140° C. (T_(g), midpoint); L100-55 0.5 J/g · ° C.(ΔC_(p)) (50:50) orange solids, dry PLM agg., irr., no B/E EudragitL100-55 (75:25) orange solids, dry PLM agg., irr., no B/E EudragitL100-55 (a): approximate ratio of Rifaximin to polymer, by weight. (b):analysis treated as non-cGMP.

TABLE 8 Physical Stability Assessment at 60° C./Dry/7 d Condition forRifaximin and Rifaximin Dispersions Prepared in Methanol by Spray DryingDescription (a) Habit/Description Analysis Results (100:0) orange solidsPLM agg., irr., no B/E Rifaximin-only (25:75) orange solids PLM agg.,irr., no B/E PVP K-90 (50:50) orange solids PLM agg., irr., no B/E PVPK-90 (75:25) orange solids PLM agg., irr., no B/E PVP K-90 (25:75) lightorange solids PLM agg., irr., no B/E HPMC-P (50:50) orange solids PLMagg., irr., no B/E HPMC-P (75:25) orange solids PLM agg., irr., no B/EHPMC-P (25:75) light orange solids PLM agg., irr., no B/E HPMC-AS HG(50:50) orange solids PLM agg., irr., no B/E HPMC-AS HG (75:25) orangesolids PLM agg., irr., no B/E HPMC-AS HG (25:75) light orange solids PLMagg., irr., no B/E HPMC-AS MG (50:50) orange solids PLM agg., irr., noB/E HPMC-AS MG (75:25) orange solids PLM agg., irr., no B/E HPMC-AS MG(25:75) light orange solids PLM agg., irr., no B/E Eudragit L100-55(50:50) orange solids PLM agg., irr., no B/E Eudragit L100-55 (75:25)orange solids PLM agg., irr., no B/E Eudragit L100-55 (a): approximateratio of Rifaximin to polymer, by weight.

TABLE 9 Parameters for Rifaximin Solid Dispersions by Spray Drying Inlettemp. Aspirator Pump Inlet temp. Outlet temp. Spray rate (b) Description(a) (set, ° C.) % % (measured, ° C.) (measured, ° C.) mL/min (50:50) 12095 40-30 120-119 60-45 9.6 HPMC-AS MG, ~10 g scale (25:75) 120 95 45-30120-119 55-43 9.7 HPMC-P, ~10 g scale (a): approximate ratio ofRifaximin to polymer, by weight. (b): flow rates are estimated at 30%pump.

TABLE 10 Characterizations of 50:50 (w/w) Rifaximin/HPMC-AS MGDispersion by Spray Drying Analysis Results XRPD x-ray amorphous mDSC154° C. (midpoint, T_(g)) 0.4 J/g · ° C. (ΔCp) TG-IR 0.5 wt % (loss upto 100° C.) 199° C. (onset, apparent decomp.) water, methanol andunknown volatiles

TABLE 11 Characterizations of 25:75 (w/w) Rifaximin/HPMC-P Dispersion bySpray Drying Analysis Results XRPD x-ray amorphous mDSC 152° C.(midpoint, T_(g)) 0.4 J/g · ° C. (ΔCp) TG-IR 1.5 wt % (loss up to 100°C.) 178° C. (onset, apparent decomp.) water and methanol

TABLE 12 Sample Information of Rifaximin Dispersions for DissolutionTest in pH 6.52 FASSIF Buffer at 37° C. Dissolution Solids Weight Volumeof Description (a) Sample ID Vessel No (mg) Buffer (mL) (50:50)4042-97-01 1 122.1 300 HPMC-AS MG 2 120.5 3 121.4 (25:75) 4103-01-01 4242.5 300 HPMC-P 5 239.2 6 242.4 (a): approximate ratio of Rifaximin topolymer, by weight.

TABLE 13 Rifaximin Concentrations of 50:50 (w/w) Rifaximin/HPMC-AS MGDispersion in pH 6.52 FASSIF Buffer at 37° C. Dissolution Time DilutionAbsorbance Concentration Vessel No (mm.) (c) (d) (μg/mL) 1 5 — 0.01590.34 10 — 0.0346 2.53 15 — 0.0569 5.13 30 — 0.09655 9.75 60 — 0.162617.46 90 — 0.2216 24.35 120 — 0.25625 28.39 1440 4 0.4093 184.99 2 5 20.02895 3.73 10 — 0.0304 2.04 15 — 0.04655 3.92 30 — 0.104 10.62 60 —0.17755 19.21 90 — 0.248 27.43 120 — 0.3065 34.25 1440 4 0.3944 178.04 35 — 0.0107 −0.26 10 — 0.02555 1.47 15 — 0.03975 3.13 30 — 0.08735 8.6860 — 0.1766 19.10 90 — 0.25815 28.61 120 — 0.32055 35.89 1440 4 0.4202190.08 (c): certain samples were diluted before analyzed to avoid thepossibility of falling outside the linearity range of the instrument.(d): absorbance data less than 0.05 is below instrument detection limitand therefore concentration calculated from such absorbance is anapproximate value.

TABL 14 Rifaximin Concentrations of 25:75 (w/w) Rifaximin/HPMC-PDispersion in pH 6.52 FASSIF Buffer at 37° C. Dissolution Time DilutionAbsorbance Concentration Vessel No (mm.) (d) (e) (μg/mL) 4 5 — 0.015550.30 10 — 0.03395 2.45 15 — 0.0528 4.65 30 — 0.12235 12.77 60 — 0.264329.33 90 — 0.37355 42.08 120 — 0.455 51.58 1440 4 0.39465 178.16 5 5 —0.0329 2.33 10 — 0.06805 6.43 15 — 0.07905 7.71 30 — 0.13745 14.53 60 —0.242 26.73 90 — 0.32595 36.52 120 — 0.40555 45.81 1440 4 0.38525 173.776 5 — 0.0155 0.30 10 — 0.057 5.14 15 — 0.09415 9.47 30 — 0.17145 18.4960 — 0.2724 30.27 90 — 0.36815 41.45 120 — 0.43155 48.84 1440 4 0.3838173.09 (d): certain samples were diluted before analyzed to avoid thepossibility of falling outside the linearity range of the instrument.(e): absorbance data less than 0.05 is below instrument detection limitand therefore concentration calculated from such absorbance is anapproximate value.

TABLE 15 Averaged Concentrations of 50:50 (w/w) Rifaximin/HPMC-AS MGDispersions in pH 6.52 FASSIF Buffer at 37° C. Con- Average DescriptionDissolution Time centration Con- Standard (a) Vessel No (min.) (μg/mL)centration Deviation (50:50) 1 5 0.34 1.27^(b) 2.154 HPMC-AS 2 3.73 MG 3−0.26 1 10 2.53 2.01^(b) 0.5284 2 2.04 3 1.47 1 15 5.13 4.06^(b) 1.008 23.92 3 3.13 1 30 9.75 9.69 0.970 2 10.62 3 8.68 1 60 17.46 18.59 0.977 219.21 3 19.10 1 90 24.35 26.80 2.202 2 27.43 3 28.61 1 120 28.39 32.853.945 2 34.25 3 35.89 1 1440 184.99 184.37 6.0455 2 178.04 3 190.08^(a)approximate ratio of Rifaximin to polymer, by weight. ^(b)absorbancedata less than 0.05 is below instrument detection limit and thereforeconcentration calculated from such absorbance is an approximate value.

TABLE 16 Averaged Concentrations of 25:75 (w/w) Rifaximin/HPMC-PDispersions in pH 6.52 FASSIF Buffer at 37° C. Con- Average DescriptionDissolution Time centration Con- Standard (a) Vessel No (min.) (μg/mL)centration Deviation (25:75) 4 5 0.30 0.98^(b) 1.171 HPMC-P 5 2.33 60.30 4 10 2.45 4.67^(b) 2.030 5 6.43 6 5.14 4 15 4.65 7.28 2.442 5 7.716 9.47 4 30 12.77 15.26 2.935 5 14.53 6 18.49 4 60 29.33 28.78 1.840 526.73 6 30.27 4 90 42.08 40.02 3.041 5 36.52 6 41.45 4 120 51.58 48.752.886 5 45.81 6 48.84 4 1440 178.16 175.01 2.749 5 173.77 6 173.09^(a)approximate ratio of Rifaximin to polymer, by weight. ^(b)absorbancedata less than 0.05 is below instrument detection limit and thereforeconcentration calculated from such absorbance is an approximate value.

TABLe 17 Analysis of Rifaximin Dispersions after Dissolution Test in pH6.52 FASSIF Buffer at 37° C. Description Dissolution (a) Vessel NoAnalysis Results (50:50) 1 PLM no B/E observed HPMC-AS MG change viewfield, no B/E 2 PLM no B/E observed change view field, no B/E 3 PLM noB/E observed majority no B/E, only 1 B/E particle in view field (25:75)4 PLM B/E flakes and blades HPMC-P 5 PLM no B/E material + B/E flakes 6PLM no B/E material + B/E flakes & blades (a): approximate ratio ofRifaximin to polymer, by weight.

ABBREVIATIONS

Type Abbreviation Full Name/Description INSTRU- XRPD x-ray powderdiffractometry MENTAL mDSC modulated differential scanning calorimetryTG-IR thermogravimetric infrared PLM polarized light microscopy UVultraviolet spectroscopy POLYMER HPMC-AS hydroxypropylmethyl celluloseacetate succinate HPMC-P hydroxypropylmethyl cellulose phthalateEudragit L100 anionic polymers with methacrylic acid as a functionalgroup, dissolution at pH > 6.0 PVP K-90 polyvinylpyrrolidone, grade K-90RESULTS T_(g) glass transition temperature ΔC_(p) heat of capacitychange amorph. amorphous agg. aggregates irr. irregular decomp.decomposition B birefringence E extinction

Example 2. Ternary Dispersion of 50:50 (w/w) Rifaximin:HPMC-AS MG

A ternary dispersion of 50:50 (w/w) Rifaximin:HPMC-AS MG with 5.9 wt %Pluronic F-127 was prepared in large quantity (containing approximately110 g of Rifaximin) by spray drying. Disclosed herein are the analyticalcharacterizations for Rifaximin ternary dispersion as-prepared andpost-stress samples at 70° C./75% RH for 1 week and 3 week, andpost-stress sample at 40° C./75% RH for 6 weeks and 12 weeks.

Characterization of Rifaximin Ternary Dispersion

Characterizations of the spray dried Rifaximin ternary dispersion (50:50(w/w) rifaximin:HPMC-AS MG with 5.9 wt % Pluronic F-127) are describedin Table 18.

TABLE 18 Characterizations of Combined Rifaximin Ternary DispersionSolids-Spray Drying Sample ID Analysis Results (b) 4103- XRPD x-rayamorphous 74-01a mDSC 136° C. (midpoint, T_(g)) 0.4 J/g · ° C. (ΔCp)TG-IR 0.7 wt % (loss up to 100° C.) 202° C. (onset, volatilization andapparent decomp.) methanol and possible acetic acid IR-ATR consistentwith structure Raman consistent with structure SEM agglomerates ofcollapsed spheres PLM irregularly-shaped equant particles PSA d10 (μm):3.627, d50 (μm): 8.233, d90 (μm): 17.530 DVS 0.13 wt % (loss at 5% RH)11.14 wt % (gain, 5-95% RH) 10.80 wt % (loss, 95-5% RH) 4074-89-01 XRPDx-ray amorphous (c) (b): temperatures are round to the nearest degree;ΔCp is rounded to one decimal places and wt % is rounded to one decimalplace.

A high resolution XRPD pattern was acquired and material is x-rayamorphous (FIG. 46). By mDSC (FIG. 47), a single apparent T_(g) isobserved from the step change in the reversing heat flow signal atapproximately 136° C. with a heat capacity change at T_(g) ofapproximately 0.4 J/g·° C.

Thermogravimetric analysis coupled with infra-red spectroscopy (TG-IR)was performed to analyze volatiles generated upon heating. The totalweight loss of sample was approximately 0.7 wt % to 100° C. and thedramatic change in the slope occurs at approximately 202° C. (FIG. 48).The Gram-Schmidt plot corresponds to the overall IR intensity associatedwith volatiles released by a sample upon heating at 20° C./min. ByGram-Schmidt, a negligible increase of intensity upon heating isobserved before ˜7 minutes followed by a dramatic increase of intensitywith the maximum at ˜11.8 min. The waterfall plot (data not shown) ofthis sample indicates volatile are released upon heating after ˜7 min(data is shown in FIG. 49 using the linked IR spectrum at different timepoints as an example) and volatiles were identified as residual methanolfrom the processing solvent in spray drying and possible acetic acidfrom HPMC-AS MG.

Vibrational spectroscopy techniques, including IR and Raman wereemployed to further characterize this ternary dispersion. The overlay ofIR spectra for the dispersion and X-ray amorphous Rifaximin is shown inFIG. 50. Based on visual inspection, two spectra are very similar.Similar observations can be drawn from the comparison of Raman analysis(FIG. 51). The sample is composed of agglomerates of collapsed spheres.Particles sizes of spheres are not uniform, ranging from slightly largerto much less than 10 μm.

PLM images (data not shown) of solids dispersed in mineral oil werecollected, which indicate sample primarily is composed ofirregularly-shaped equant particles approximately 5-15 μm in length withsome agglomerates 20-50 μm in length. Particle size analysis (FIG. 52)indicates that 50% of particles have size less than 8.233 μm and 90% ofparticles have size less than 17.530 μm. Data was acquired in 2% (w/v)Lecithin in Isopar G.

The DVS isotherm of solids is shown in FIG. 53. The material exhibits a0.13 wt % loss upon equilibration at 5% RH. Solids then gain 11.14 wt %between 5% and 95% RH and exhibits some hysteresis with 10.80 wt % lossupon desorption from 95% to 5% RH. XRPD analysis of the solids recoveredafter completion of the desorption step showed no evidence of sharppeaks indicative of a crystalline solid (FIG. 54).

Physical Stability Assessment on Rifaximin Ternary Dispersion

An assessment of physical stability of this rifaximin ternary dispersionis currently in progress by exposing solids to varied elevatedtemperature/relative humidity conditions, including 25° C./60% RH, 40°C./75% RH and 70° C./75% RH for extended period of time. At designatedtime interval, such as at 1 week, 3 week, 6 week, and 12 weeks, selectedsamples were removed from stress conditions for characterization.

Table 19 summarized characterization results for the samples thatstressed at 70° C./75% RH condition 1 week and 3 weeks, and the samplethat stressed at 40° C./75% RH condition 6 weeks.

TABLE 19 Physical Stability Evaluation on Rifaximin Ternary DispersionHabit/ Condition Time Description Analysis Results (a) 70° C./75% RH 1week orange solids, XRPD x-ray amorphous aggregates, no mDSC 134° C.(midpoint, T_(g)) B/E 0.4 J/g · ° C. (ΔCp) SEM agglomerates of collapsedspheres KF 3.80% 70° C./75% RH 3 weeks dark orange XRPD x-ray amorphoussolids, mDSC 134° C. (midpoint, T_(g)) aggregates, no 0.4 J/g · ° C.(ΔCp) B/E SEM agglomerates of collapsed spheres KF 3.19% 40° C./75% RH 6weeks orange solids, XRPD x-ray amorphous aggregates, no mDSC 133° C.(midpoint, T_(g)) B/E 0.4 J/g · ° C. (ΔCp) SEM agglomerates of collapsedspheres KF 4.05% 40° C./75% RH 12 weeks orange solids, XRPD x-rayamorphous aggregates, no mDSC 132° C. (midpoint, T_(g)) B/E 0.5 J/g · °C. (ΔCp) SEM agglomerates of collapsed spheres KF 3.37% (a):temperatures are round to the nearest degree; ΔCp is rounded to onedecimal places.

For a sample that was stressed at 70° C./75% RH for 1 week, solids arestill x-ray amorphous according to XRPD (FIG. 55). A single T_(g) atapproximately 134° C. was observed from the apparent step change in thereversing heat flow signal in mDSC with the change of heat capacity 0.4J/g ° C., indicating the components of each dispersion remainedintimately miscible after stress (FIG. 56). A non-reversible endothermwas observed at approximately 54° C. which is likely due to the residualsolvent from spray drying and moisture that materials absorbed duringstress, which is confirmed by KF analysis that sample contains 3.80 wt %of water (KF analysis for Rifaximin ternary dispersion after 70° C./75%RH 1 week; 1.2855 g—R1=3.72 and 0.988 g—R1=3.87%). The sample iscomposed of agglomerates of collapsed spheres and particles sizes ofspheres are not uniform, which is similar to the as-prepared material.

For the sample that was stressed at 70° C./75% RH for 3 weeks, althoughthe color of the material appeared to be darker than the 1-week sample,characterization results for 3-week sample are similar to that for1-week sample. Solids are also x-ray amorphous by XRPD (FIG. 55) anddisplay a single T_(g) at approximately 134° C. by mDSC (FIG. 57). KFanalysis indicates it contains 3.19 wt % of water (KF analysis forrifaximin ternary dispersion after 70° C./75% RH 3 weeks; 1.2254g—R1=3.45 and 1.1313 g—R1=2.93). By SEM (data not shown), the materialhas morphology similar to the as-prepared dispersion and 1-week stresssample, which is composed of agglomerates of collapsed spheres andparticles sizes of spheres are not uniform.

For the sample that was stressed at 40° C./75% RH for 6 weeks, solidsare still x-ray amorphous according to XRPD (FIG. 55). It has a singleT_(g) at approximately 133° C. by mDSC with the change of heat capacity0.4 J/g ° C. (FIG. 58). It contains 4.05 wt % of water by KF (KFanalysis for rifaximin ternary dispersion after 40° C./75% RH 6 weeks;1.0947 g—R1=3.47 and 1.2030—R1=4.63). By SEM (data not shown), thesample is composed of agglomerates of collapsed spheres and particlessizes of spheres are not uniform, which is similar to the as-preparedmaterial.

For the sample that was stressed at 40° C./75% RH for 12 weeks, solidsare x-ray amorphous (FIG. 55) and display a single T_(g) atapproximately 132° C. with the change of heat capacity 0.5 J/g ° C.(FIG. 59). It contains 3.37 wt % of water by KF (KF analysis forRifaximin ternary dispersion after 40° C./75% RH 12 weeks; 1.3687g—R1=3.06 and 1.1630 g—R1=3.67). SEM analysis (data not shown) indicatesthat the sample is composed of agglomerates of collapsed spheres andparticles sizes of spheres are not uniform, which is similar to theas-prepared material.

Example 3. Rifaximin Solid Dispersion Composition and ProceduresRifaximin Ternary Dispersion Ingredients:

Rifaximin ternary dispersions (50:50 w/w Rifaximin:HPMC-AS MG with 5.9wt % Pluronic F-127) were prepared from methanol using spray drying inclosed mode suitable for processing organic solvents. Ingredients arelisted as below in Table 20:

TABLE 20 Components of Rifaximin Solid Dispersion Component mg/g PurposeRifaximin 472 active pharmaceutical ingredient Hydroxypropylmethyl 472stabilizing agent cellulose acetate succinate (HPMC-AS), Type MGPluronic F-127 56 wetting agent Methanol — volatile; removed duringprocess

Spray Drying Procedures:

Rifaximin ternary dispersions were prepared by spray drying in bothsmall scale (˜1 g API) and large scale (≥34 g API in a single batch).

For the small-scale sample, rifaximin and then the methanol were addedto a flask. The mixture was stirred at ambient temperature for ˜5 min togive a clear solution. HPMC-AS MG and Pluronic F-127 were added insuccession and the sample was stirred for ˜1 hr. An orange solution wasobtained.

For large-scale samples, a solution was prepared at ˜40° C. Rifaximinand then methanol were added to a flask and the mixture was stirred at˜40° C. for ˜5 min until clear. HPMC-AS MG, and then Pluronic F-127 wereadded into the rifaximin solution under stirring at ˜40° C. The samplecontinued to stir for ˜1.5 hr to 2 hr at this temperature. A dark redsolution was obtained. The sample was removed from the hot plate andleft at ambient to cool.

Experimental conditions to prepare Rifaximin ternary solutions aresummarized in Table 21 below:

TABLE 21 Experimental Conditions to Prepare Rifaximin Ternary Solutionsweight Concen- (API/HPMC AS tration Solvent MG/Pluronic F127, g)Temperature (g/L) methanol, 100 mL 1.0535/1.0529/0.1249 ambient 22.3methanol, 1000 mL 34.07/34.07/4.02 ~40° C. 72.2 methanol, 1250 mL50.34/50.32/5.94 ~40° C. 85.3 methanol, 1250 mL 50.16/50.14/5.92 ~40° C.85 methanol, 1250 mL 50.05/50.06/5.91 ~40° C. 85

During the spray drying process, both the small and large scalerifaximin ternary solutions were kept at ambient temperature. The pump %was decreased during the process in an attempt to control outlettemperature above 40° C. The operating parameters used for processingare presented in Table 22 below.

TABLE 22 Operating Parameters Used For Processing Rifaximin SD InletSpray rate temp. Aspirator Pump Inlet temp. Outlet temp. (b) Description(a) (set, ° C.) % % (measured, ° C.) (measured, ° C.) mL/min 50:50 12095 35 120 60-55 10.4 Rifaximin:HPM 120 95 65-30 120-119 61-42 23 C-AS MG120 95 50-30 120-119 67-43 16 5.9 wt % 120 95 50-30 120-119 65-43 16Pluronic F-127 120 95 50-30 120-119 67-43 16 (a): 50:50 is approximateratio of Rifaximin to polymer, by weight; 5.9 wt % Pluronic is weightfraction to 50:50 rifaximin:HPMC-AS MG dispersion. (b): Flow rates areestimated. Flow rate for 4103-41-01 was measured at pump 35%; for4103-56-01 was measured at pump 65%, while for others were measured atpump 50%.

Solids recovered after spray drying were dried at 40° C. under vacuumfor 24 hours and then stored at sub-ambient temperatures over desiccant.

Spray Drying Process Parameters:

-   -   Spray Dryer—PSD 1    -   Two Fluid Niro Nozzle    -   Nozzle orifice—1 mm    -   Inlet gas temperature—125±5 deg C.    -   Process gas flow (mmH2O)—44    -   Atomizing gas pressure—0.7-1 bar    -   Feed rate—4.7 kg/Hr    -   Outlet temperature—55±3 deg C.    -   Solution temperature—36 deg C.    -   Post spray drying vacuum dry at 40 deg C. for 48 hrs

Example 4

Exemplary formulations for micronized, API, amorphous, solid dispersionand micronized capsules are below in Table 23. These capsules were usedin the dog study of Example 5.

TABLE 23 Capsule Formulation composition (Solid Dispersion (SD)Capsules) Micronized Amorphous Micronized Capsules API Capsules CapsulesSD Capsules Tablets Ingredients % g/dose % g/dose % g/dose % g/dose %g/dose Rifaximin 95.5 2.2 47.2 2.2 51.7 2.2 42.47 2.2 50 2.2 Ac-di-sol4.5 0.1 5 0.23 5 0.21 10.02 0.52 7.5 0.33 Mannitol 160C 47.8 2.23 43.31.84 Pluronic 188 5.04 0.26 HPMC AS 42.47 2.2 Avicel 113 26 1.14 Avicel112 15 0.66 Magnesium 1 0.04 Stearate Cab-o-sil 0.5 0.02 Avicel CL-611Mannitol 160C Total 100 2.3 100 4.66 100 4.26 100 5.18 100 4.4

TABLE 24 Manufacture of rifaximin/HPMC-AS/Pluronic 275 mg Capsules % mg/Theo. Actual Component Formula caps Qty (g) Qty (g) Rifaximin 42.47 275113.7 113.7 HPMC-AS 42.47 275 113.7 113.7 (type MG) Pluronic F-127 5.0432.63 13.49 13.49 Sodium 10.02 64.87 26.82 26.82 Croscarmellose HardGelatin 1 N/A 300 300 Capsule (size 000) Clear Total 100 647.5 267.7 g

Blending/Encapsulation Procedure:

To form the capsules sodium croscarmellose was added to the bag of SDrifaximin dispersion and bag blend for 1 minute, and then the materialwas added to the V-blender and blended for 10 minutes at 24 rpm.

The material was then discharged into a stainless steel pan and recordthe height of material in the pan. Empty capsules were tared using ananalytical balance, then the capsules were filled by depressing into thebed of material. The weight is adjusted within + or −5% of target fillweight of 647.5 mg (acceptable fill range 615.13-679.88 mg).

FIGS. 61-63 show the rifaximin solid dispersion (SD) capsules in variousbuffers; with and without SDS; and compared to amorphous rifaximin. FIG.61 shows results of dissolution studies of rifaximin SD capsules in acidphase: 0.1 N HCl with variable exposure times in a buffer containing0.45% SDS at pH 6.8. FIG. 62 shows results of dissolution studies ofrifaximin SD capsules in acid phase for 2 hours buffered at pH 6.8 withand without SDS. FIG. 63 shows results of dissolution studies ofrifaximin SD capsules in acid phase in a phosphate buffer at pH 6.8 with0.45% SDS compared to amorphous rifaximin. As shown in the FIGS. 61-63rifaximin SD near 100% dissolution is achieved in 0.45% SDS and the SDformulation dissolves more slowly than the amorphous rifaximin.

Example 5. Pharmacokinetic (PK) Studies of Solid Dispersion in Capsules

Presented herein are dog pharmacokinetics (PK) studies comparing variousforms of rifaximin. PK following administration of rifaximin API incapsule, micronized API in capsule, nanocrystal API in capsule(containing surfactant), amorphous in capsule, and solid dispersion (SD)in capsule were tested.

In the SD dosage form, the polymer used was HPMC-AS at a drug to polymerratio of 50:50. The formulation also comprised pluronic F127 andcrosscarmellose sodium (see Example 4).

A brief study design: male beagle dogs (N=6, approximately 10 kg)received rifaximin 2200 mg in the dosage forms described above as asingle dose (capsules, 275 mg, 8 capsules administered in rapidsuccession), in a cross-over design with one week washout betweenphases. Blood was collected at timed intervals for 24 h after dosageadministration, and plasma was harvested for LC-MS/MS analysis. The meanconcentrations are shown in FIG. 60.

Table 25 shows the PK parameters. From the table it can be seen thatsystemic exposure of the solid dispersion formulation is greater thanthat of amorphous or crystalline form (API) of rifaximin.

TABLE 25 PK Parameters of API, Amorphous and Solid Dispersion to DogsHalf-life* Tmax Cmax AUClast AUCINF_obs AUC_0-24 ID h h ng/mL h*ng/mLh*ng/mL h*ng/mL 901_API 16.76 0.5 65.5 101 118 101 902_API 9.41 1 3.8325 29 25 903_API 10.03 1 197 344 360 344 904_API 3.56 1 1.21 5 6 6905_API 2.94 1 1.53 5 6 6 906_API 24 0.52 7 7 mean 6.98 1 44.93 81 10482 SD [0.5-24]  78.75 134 150 134 901_amorph 5.38 1 536 1407 1421 1407902_amorph 5.93 2 4100 12258 12762 12258 903_amorph 6.25 2 1050 33753523 3375 904_amorph 4.77 2 763 2291 2306 2291 905_amorph 7.72 1 12002041 2059 2041 906_amorph 5.63 2 704 2076 2090 2076 mean 5.88 2 1392.173908 4027 3908 SD [1-2] 1348.24 4141 4334 4141 901_SD amorph 6.66 2 4911354 1394 1354 902_SD amorph 2.04 2 6550 25140 25149 25140 903_SD amorph2.8 4 2410 10490 10508 10490 904_SD amorph 2.24 1 1410 6343 6350 6343905_SD amorph 3.97 2 2860 7885 7895 7885 906_SD amorph 4.89 2 1900 45324558 4532 mean 3.01 2 3026 10878 10892 10878 SD [1-4] 2043.58 8267 82648267 *geometric mean **median and range

API exposures were low, in keeping with what has been previouslyobserved for rifaximin. In contrast, mean exposures (AUCinf) followingamorphous and SD rifaximin administration were substantially higher,with ˜40- and ˜100-fold greater exposure, respectively, as compared withAPI. Variability was high in all three dose groups. In general, theshapes of all three profiles were similar, suggesting effects of thedosage forms on bioavailability without effects on clearance or volumeof distribution.

Example 6. Human Clinical Studies

Rifaximin SDD with 10% CS formulation was used in human clinicalstudies. FIG. 65A-B show the kinetic solubility of rifaximin SD granules10% wt CS FaSSIF or 10% wt CS FeSSIF (a) and the dissolution profiles ofSDD tablet 10% CS in 0.2% SLS at pH 4.5, 5.5 and 7.4. As shown in FIG.65A-B, rifaximin SDD 100%, or near 100%, dissolution is achieved in 0.2%SLS, pH 4.5, 5.5 and 7.4. FIG. 66A-B show that release can be delayed upto two hours and extended up to three hours.

Example 7. Effects of Media pH on Dissolution

FIG. 67A-B, FIG. 68A-B, FIG. 69A-B, and FIG. 70A-B show the effects ofmedia pH on Rifaximin SDD tablet SDD tablet dissolution at variouslevels of CS: 0%, 2.5%, 5%, and 10% CS. FIG. 67A-B and FIG. 68A-B showdissolution profiles of SDD tablet with 0%, 2.5%, 5% or 10% CS in 0.2%SDS at 2 hours pH 2.0, pH 4.5, 0.2% SDS pH 5.5, or 0.2% SDS, pH 7.4.FIG. 69A-B and FIG. 70A-B show the dissolution profiles of SDD tablet2.5% CS, 0% CS, 10% CS and 5% CS in 0.2% SLS, pH4.5, 0.2% SLS, pH 5.5and 0.2% SLS, pH 7.4. FIG. 71A-B show CS release mechanism.

Example 8

Described herein are the preparation and characterization of rifaximinquaternary dispersions with antioxidants. Antioxidants used werebutylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT) andpropyl gallate (PG).

Sample preparation and Characterization

Three rifaximin quaternary samples were prepared by spray drying frommethanol. Spray drying parameters are summarized in Table 26. Table 2Parameters for Samples Prepared by Spray Drying

TABLE 26 Inlet Outlet Spray temp. Inlet temp. temp. rate (set, AspiratorPump (measured, (measured, (a) Sample ID ° C.) % % ° C.) ° C.) mL/min0.063 wt % 120 95 45-35 120-124 61-49 19 of BHA in the dispersion 0.063wt % 120 95 45-35 120-121 60-50 20 of BHT in the dispersion 0.094 wt %120 95 45-35 119-120 60-48 20 of propyl gallate in the dispersion (a):flow rates are estimated based on initial pump % of 45%.

TABLE 27 Characterization of Rifaximin Quaternary SamplesHabit/Description Analysis Results (b) orange solids, XRPD x-rayamorphous irregular mDSC 133° C. (midpoint, T_(g)) aggregates, no B/E0.3 J/g · ° C. (ΔCp) orange solids, XRPD x-ray amorphous irregular mDSC133° C. (midpoint, T_(g)) aggregates, no B/E 0.4 J/g · ° C. (ΔCp) orangesolids, XRPD x-ray amorphous irregular mDSC 134° C. (midpoint, T_(g))aggregates, no B/E 0.4 J/g · ° C. (ΔCp)

A small sub-lot from each of spray dried materials was visuallyinspected by PLM and then characterized by XRPD and mDSC.Characterization results are summarized in Table 27. The preparedmaterials are x-ray amorphous, as shown in FIG. 72 the overlay of XRPDpatterns, which agree with their PLM observations.

In the mDSC, each of material displays a single apparent T_(g) in thereversing heat flow signal at approximately 133° C. (FIG. 73, with 0.063wt % BHA), 133° C. (FIG. 74, with 0.063 wt % BHT), and 134° C. (FIG. 75,with 0.094 wt % PG), which is consistent with the T_(g) of the spraydried rifaximin ternary dispersion of 47.2:47.2:5.6 w/w/w/rifaximin/HPMC-AS MG/Pluronic F-127 (135 or 136° C.).

Example 9: Rifaximin Solid Dispersions

This example sets forth exemplary microgranules of rifaximin andpharmaceutical compositions comprising the same.

Spray dry dispersion (SDD), solid dispersion, amorphous solid dispersionare used interchangabley herein to refer to the rifaximin formulations.

The complete statement of the components and quantitative composition ofRifaximin Solid Dispersion Formulation (Intermediate) is given in Table28

TABLE 28 Composition of Rifaximin Solid Dispersion Formulation ComponentQuantity (%) Function Rifaximin Drug 42.48 Active Ingredient SubstanceHypromellose Acetate 42.48 Solubility Enhancer Succinate (HPMC-AS)Poloxamer 407 5.04 Surfactant Croscarmellose 10.00 Dissolution EnhancerSodium

Composition of Rifaximin Solid Dispersion IR Capsule

TABLE 29 Composition of Rifaximin solid dispersion IR capsule ComponentQuantity Function Rifaximin solid dispersion 75 mg-275 mg* Activeingredient (amorphous) Hard Gelatin capsules 1 unit Capsule Coni-Snap,Size 000, Transparent *Rifaximin dose equivalent

Description of Manufacturing Process and Process Controls ManufacturingProcess for Rifaximin Solid Dispersion Formulation Table 30 Sets Forththe Manufacture of Rifaximin Solid Dispersion Microgranules

TABLE 30 Component Process Methanol Rifaximin HPMC-AS Poloxamer 407

Feed Solution

Croscarmellose Sodium

Manufacturing Process for Rifaximin Solid Dispersion IR Capsules

The manufacturing process the Rifaximin solid dispersion IR capsules isgiven in Table 31.

TABLE 31 Manufacture of Rifaximin solid dispersion microgranules in IRcapsules Component Process Rifaximin solid dispersion Formulation

Exemplary spray drying processes are set forth in Table 32.

TABLE 32 Spray Drying Process: Spray Dryer—PSD 1 Two Fluid Niro NozzleNozzle orifice—1 mm Inlet gas temperature—125 ± 3 deg C. Process gasflow (mmH2O)—44 Atomizing gas pressure—1 bar Feed rate—4.7 kg/Hr Outlettemperature—55 ± 3 deg C. Solution temperature—36 deg C. Post spraydrying vacuum dry at 40 deg C. for 48 hrs Micronized Amorphous AmorphousMicronized Caps API Caps Caps SD caps Tab Ingredients % g/dose % g/dose% g/dose % g/dose % g/dose Rifaximin 95.5 2.2 47.2 2.2 51.7 2.2 42.472.2 50 2.2 Ac-di-sol 4.5 0.1 5 0.23 5 0.21 10.02 0.52 7.5 0.33 Mannitol47.8 2.23 43.3 1.84 160C Pluronic 5.04 0.26 188 HPMC AS 42.47 2.2 Avicel113 26 1.14 Avicel 112 15 0.66 Magnesium 1 0.04 Stearate Cab-o-sil 0.50.02 Avicel CL- 611 Mannitol 160C Total 100 2.3 100 4.66 100 4.26 1005.18 100 4.4

Example 10: Characterization of Drug Product Samples ContainingRifaximin Solid Dispersion

Disclosed herein is dissolution data for roller compacted materials ofSolid Dispersion Rifaximin with varying levels (0, 2.5%, 5%, and 10%) ofcroscarmellose sodium.

Three roller compacted material of Amorphous Solid Dispersion Rifaximinwith varying levels (0, 2.5%, 5%) of croscarmellose sodium weredissolution tested. Results are compared to dissolution of the rifaximingranules with 10% croscarmellose sodium.

Dissolution Studies with USP Paddle Method

Dissolution tests were performed on as received roller compactedmaterials of Solid Dispersion Rifaximin with 0, 2.5 wt %, and 5 wt %croscarmellose sodium. Powders of solids were directly added into pH 6.5FaSSIF buffer with gentle agitation of the media (50 rpm paddle stirrer)at 37° C. for 24 hrs.

At designated time points of 5, 10, 20, 30, 60, 90, 120, 240 and 1440minutes, aliquots were removed from each of the samples. Analysis of thedate indicates that an increase in rifaximin concentration is apparentwith the rising croscarmellose sodium level in materials, particularlyin the early stage of the dissolution. After 24 hrs, the rifaximinconcentration from granules containing 5 wt % croscarmellose sodium issimilar to granules with 10 wt % croscarmellose sodium.

Example 11: Characterization of Rifaximin Solid Dispersion Powder 42.48%w/w

Described herein is the characterization of Rifaximin Solid DispersionPowder 42.48% w/w. Dissolution testing was also performed on thematerial at pH 6.5 in FaSSIF at 37° C.

A sample of rifaximin ternary dispersion was characterized by XRPD,mDSC, TG-IR, SEM and KF.

X-ray powder diffraction (XRPD) analysis using a method for RifaximinSolid Dispersion Powder 42.48% w/w was conducted. The XRPD pattern byvisual inspection is x-ray amorphous with no sharp peaks (FIG. 76). BymDSC a single apparent T_(g) is observed from the step change in thereversing heat flow signal at approximately 134° C. with a heat capacitychange at T_(g) of approximately 0.36 J/g·° C.

Thermogravimetric analysis coupled with infra-red spectroscopy (TG-IR)was performed to analyze volatiles generated upon heating. The totalweight loss of sample was approximately 0.4 wt % to 100° C., and adramatic change in the slope occurs at approximately 190° C. which islikely due to decomposition. The Gram-Schmidt plot corresponds to theoverall IR intensity associated with volatiles released by a sample uponheating at 20° C./min. Gram-Schmidt indicates that volatiles arereleased upon heating after ˜8 min, and volatiles were identified asresidual methanol from the processing solvent in spray drying andpossible acetic acid from HPMC-AS MG.

KF analysis indicates that the material contains 1.07 wt % water[(1.00+1.13)/2=1.07%].

Example 12: Methods for Spray Drying Rifaximin Ternary Dispersion (50:50w/w Rifaximin:HPMC-AS MG with 5.9 wt % Pluronic F-127)

Provided herein are procedures to spray dry Rifaximin ternary dispersion(50:50 w/w Rifaximin:HPMC-AS MG with 5.9 wt % Pluronic F-127).

Rifaximin ternary dispersions (50:50 w/w Rifaximin:HPMC-AS MG with 5.9wt % Pluronic F-127) were prepared from methanol using Büchi B-290 MiniSpray Dryer in closed mode suitable for processing organic solvents.Ingredients are listed in Table 33 below:

TABLE 33 No. Component mg/g Purpose 1 Rifaximin 472 activepharmaceutical ingredient 2 Hydroxypropylmethyl cellulose 472stabilizing agent acetate succinate (HPMC-AS), Type MG 3 Pluronic F-12756 wetting agent 4 Methanol — volatile; removed during process

Rifaximin ternary dispersions were prepared by spray drying in bothsmall scale (˜1 g API) and large scale (≥34 g API in a single batch).

For a small-scale sample, rifaximin and then the methanol were addedinto a clean flask. The mixture was stirred at ambient for ˜5 min togive a clear solution. HPMC-AS MG and Pluronic F-127 were added insuccession and the sample was stirred for ˜1 hr. An orange solution wasobtained.

For a large-scale sample, a solution was prepared at ˜40° C. Rifaximinand then methanol were added to a clean flask and the mixture wasstirred at ˜40° C. for ˜5 min until clear. HPMC-AS MG, and then PluronicF-127 were added into the rifaximin solution under stirring at ˜40° C.The sample continued to stir for ˜1.5 hr to 2 hr at this temperature. Adark red solution was obtained. The sample was removed from the hotplate and left at ambient to cool.

Experimental conditions to prepare Rifaximin ternary solutions aresummarized in Table 34 below:

TABLE 34 weight Concen- (API/HPMC AS MG/ tration Solvent Pluronic F127,g) Temperature (g/L) methanol, 100 mL 1.0535/1.0529/0.1249 ambient 22.3methanol, 1000 mL 34.07/34.07/4.02 ~40° C. 72.2 methanol, 1250 mL50.34/50.32/5.94 ~40° C. 85.3 methanol, 1250 mL 50.16/50.14/5.92 ~40° C.85.0 methanol, 1250 mL 50.05/50.06/5.91 ~40° C. 85.0

During spray drying process, both the small and large scale rifaximinternary solutions were kept at ambient temperature. The Pump % wasdecreased during process in attempt to control outlet temperature above40° C. The operating parameters used for processing are presented inTable 35 below.

TABLE 35 Inlet temp. Aspirator Pump Inlet temp. Outlet temp. Spray rate(b) Description (a) (set, ° C.) % % (measured, ° C.) (measured, ° C.)mL/min 50:50 120 95 35 120 60-55 10.4 Rifaximin:HPMC-AS 120 95 65-30120-119 61-42 23 MG 120 95 50-30 120-119 67-43 16 5.9 wt % PluronicF-127 120 95 50-30 120-119 65-43 16 120 95 50-30 120-119 67-43 16 (a):50:50 is approximate ratio of Rifaximin to polymer, by weight; 5.9 wt %Pluronic is weight fraction to 50:50 Rifaximin:HPMC-AS MG dispersion.(b): flow rates are estimated. Flow rate for 4103-41-01 was measured atpump 35%; for 4103-56-01 was measured at pump 65%, while for others weremeasured at pump 50%.

Solids recovered after spray drying were dried at 40° C. under vacuumfor 24 hours and then stored at sub-ambient (freezer) over desiccant.

Example 13. Non-Clinical Data-Form/Formulation Comparison and DoseRanging in Dogs

Described herein is non-clinical data, form/formulation comparison indogs and SDD dose ranging in dogs. FIG. 77 indicates the results of twostudies conducted to characterize the pharmacokinetics of rifaximinfollowing administration of varying forms and formulations following asingle oral dose. Blood samples were collected at timed intervals overthe 24 h after single dose administration (2200 mg total dose in eachcase) and processed to plasma for analysis of rifaximin concentrations.PK parameters were estimated by noncompartmental methods. The resultsare shown in FIG. 77. Of the forms/formulations shown, the spray-drieddispersion showed that the highest exposure, and therefore the highestbioavailability, resulted from administration of the SDD formulation(dosed as SDD powder in gelatin capsules). In order of decreasingexposure among forms dosed in gelatin capsule formulation,SDD>amorphous>iota>micronzed>eta>current crystalline API. Lower insystemic exposure than all of those are the micronized suspensionformulation (reconstituted powder for oral suspension) and the current550 mg Xifaxan tablet. Table 36, below, shows Pk parameters for dogforms.

TABLE 36 Tmax Cmax AUCall AUCINF_obs HL_Lambda_z h h ng/mL h*ng/mLh*ng/mL Eta 9.70 1.5 162.28 434.14 608.14 Iota 6.56 2 276.50 718.23739.94 Amorphous 5.82 2 1392.17 3907.84 4026.86 API capsules 5.64 144.93 81.20 103.83 SDD 3.16 2 2603.50 9290.71 9308.83 Micronizedcapsules 8.10 1 473.43 894.65 905.97 Micronized suspension 5.22 3 0.685.11 8.41 Micronized tablets 4.77 5 0.83 6.81 10.20 Nanocrystal capsules5.01 5 0.99 9.05 8.70

FIG. 78 shows the results of the dog dose escalation, in which dogsreceived single doses of the SDD formulation in capsules, at doses from150 mg to 2200 mg. The results indicate an essentially linear doseescalation (increases in exposure that are approximately proportional toincrease in dose) up to 550 mg, followed by a greater-than-proportionalincrease at 1100 mg and 2200 mg. This is quite unusual in the linearrange in that the current crystalline form of rifaxmin does not doseescalate, generally, exposure does not increase substantially onincreasing dose. The greater than dose proportional increase onincreasing dose is also remarkable and suggests that, at the higherdoses, rifaximin is saturating intestinal P-glycoprotein transport thatwould otherwise limit systemic absorption, thereby allowing increasedabsorption.

Example 14. Human Studies

Described herein are clinical studies carried in ten male humansubjects. FIG. 79 sets out the quotient study design for rifaximin SDDdose escalation. FIG. 80 outlines the dose escalation/regionalabsorption study, dose escalation/dose selection. FIGS. 81 and 82 showrepresentative subject data from an exemplary dose escalation study.Mean data (linear scale and log scale) is shown in FIGS. 83 and 84,respectively. Mean profiles, log scale. Terminal phases are parallel, inclearance mechanisms. A summary of rifaximin SDD dose escalation isshown indicating that it is likely that there is not saturation of anymetabolic or other systemic FIG. 85. To summarize, there are roughlydose proportional increases in exposure (C_(max) and AUC) with increasesin dose, as shown by C_(max) multiple and AUC multiple columns. T_(max)is not delayed by dose increases, further indicating an early absorptionwindow (corroborated by regional absorption data). The percent of dosein urine is remarkable in that it stays low, approximately 0.2% or lessof the dose excreted over 24 h. This result is surprising in that thisis quite low in spite of the significant increases in systemic exposureas compared with the crystalline formulation. Taken together, theresults indicate a considerably increased solubility that presumablyleads to increased local/lumenal soluble rifaximin, with accompanyingincreases in systemic exposure, but without significant increases inurinary excretion that are reflective of percent of rifaximin doseabsorbed.

Dose/dosage form comparisons are shown in FIGS. 86 and 87. The tablescompare SDD at increasing doses to the current crystalline formulationin terms of systemic PK. As noted in FIG. 87, as compared to the PK ofrifaximin from the current formulation, the SDD formulation at the samedose shows an approximate 6.4-fold increase in C_(max) and anapproximate 8.9-fold increase in AUC. Nonetheless, these exposures areless than those observed in any hepatic impaired subject with thecurrent tablet formulation.

Example 15. Exemplary Tablet Formulations

According to certain exemplary embodiments, microgranules, blends andtablets are formulated as set forth in Table 37, below

Rifaximin 5DD Granules % w/w % w/w % w/w % w/w Component Function (0%CS) (2.5% CS) (5% CS) (10% CSf Rifaximin Drug 47.2 46.02 44.84 42.48HPMC-AS Polymer 47.2 46.02 44.84 42.48 Pluronic F-127 Wetting agent 5.65.46 5.32 5.04 Croscarmellose Rate 0 2.5 5 10 Na (CS) controlling Total100 100 100 100

Granule Blend mg/Tab mg/Tab mg/Tab mg/Tab Roller Compacted Granules635.59 652.34 669.05 706.21 Granules Avicel PH102 Filler 166 149.18132.52 95.38 Croscarmellose Na Disintegrant 42.5 42.5 42.5 42.5(Extra-granuler) Cab-O-Sil Glidant 1.7 1.7 1.7 1.7 Magnesium StearateLubricant 4.25 4.25 4.25 4.25 Total 850.04 849.97 850.02 850.04

Overall Rifaximin Tablet Composition % w/w % w/w % w/w % w/w ComponentFunction (0% CS) (2.5% CS) (5% CS) (10% CS) Rifaximin Drug 35.29 35.3235.29 35.29 HPMC-AS Polymer 35.29 35.32 35.29 35.29 Pluronic F-127Wetting agent 4.19 4.19 4.19 4.19 Croscarmellose Rate 0.00 1.92 3.948.31 Na (intra- controlling granuler} Avicel PH102 Filler 19.53 17.5515.59 11.22 Croscarmellose Disintegrant 5.00 5.00 5.00 5.00 Na (Extra-granuler) Cab-O-Sil Glidant 0.20 0.20 0.20 0.20 Magnesium Lubricant 0.500.50 0.50 0.50 Stearate Total 100 100 100 100

1-12. (canceled)
 13. A method of treating a bowel related disorder in asubject in need thereof, comprising administering to the subject a soliddispersion comprising rifaximin and a polymer, wherein the polymercomprises from about 10% to about 60% by weight of the solid dispersionand is selected from the group consisting of polyvinylpyrrolidone (PVP)grade K-90, hydroxypropylmethyl cellulose phthalate (HPMC-P) grade 55,hydroxypropyl methylcellulose acetate succinate (HPMC-AS) grades HG andMG, and polymethacrylate, and wherein said solid dispersion comprises anon-crystalline fully miscible dispersion comprising said rifaximin andsaid polymer.
 14. The method of claim 13, wherein the bowel relateddisorder is irritable bowel syndrome.
 15. The method of claim 13,wherein the bowel related disorder is hepatic encephalopathy.
 16. Thesolid dispersion of claim 13, wherein said rifaximin and said polymerare present in equal amounts, and each of said rifaximin and saidpolymer comprises from about 10% to about 50% by weight of said soliddispersion.
 17. The solid dispersion of claim 14, wherein said rifaximinand said polymer are present in equal amounts, and each of saidrifaximin and said polymer comprises from about 10% to about 50% byweight of said solid dispersion.
 18. The solid dispersion of claim 15,wherein said rifaximin and said polymer are present in equal amounts,and each of said rifaximin and said polymer comprises from about 10% toabout 50% by weight of said solid dispersion.
 19. The solid dispersionof claim 13, wherein said polymer comprises HPMC-AS grade MG or HPMC-ASgrade HG.
 20. The solid dispersion of claim 14, wherein said polymercomprises HPMC-AS grade MG or HPMC-AS grade HG.
 21. The solid dispersionof claim 15, wherein said polymer comprises HPMC-AS grade MG or HPMC-ASgrade HG.
 22. The solid dispersion of claim 16, wherein said polymercomprises HPMC-AS grade MG or HPMC-AS grade HG.
 23. The solid dispersionof claim 17, wherein said polymer comprises HPMC-AS grade MG or HPMC-ASgrade HG.
 24. The solid dispersion of claim 18, wherein said polymercomprises HPMC-AS grade MG or HPMC-AS grade HG.
 25. The solid dispersionof claim 13, wherein said non-crystalline fully miscible dispersionfurther comprises a non-ionic surfactant.
 26. The solid dispersion ofclaim 14, wherein said non-crystalline fully miscible dispersion furthercomprises a non-ionic surfactant.
 27. The solid dispersion of claim 15,wherein said non-crystalline fully miscible dispersion further comprisesa non-ionic surfactant.
 28. The solid dispersion of claim 16, whereinsaid non-crystalline fully miscible dispersion further comprises anon-ionic surfactant.
 29. The solid dispersion of claim 19, wherein saidnon-crystalline fully miscible dispersion further comprises a non-ionicsurfactant.